Current use of existing antiviral drugs for COVID-19 [56].
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"8613",leadTitle:null,fullTitle:"Aerospace Engineering",title:"Aerospace Engineering",subtitle:null,reviewType:"peer-reviewed",abstract:"This book is a collection of reviewed and relevant research chapters, offering a comprehensive overview of recent developments in the field of engineering. The book comprises chapters authored by various researchers and edited by an expert active in the aerospace engineering research area. All chapters are separate but united under a common research study topic. This publication aims at providing a thorough overview of the latest research efforts by international authors on engineering, and opening new possible research paths for further novel developments.",isbn:"978-1-83962-786-6",printIsbn:"978-1-83962-784-2",pdfIsbn:"978-1-83962-787-3",doi:"10.5772/intechopen.79206",price:119,priceEur:129,priceUsd:155,slug:"aerospace-engineering",numberOfPages:228,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"075278075d72ebe02490ff58675119ef",bookSignature:"George Dekoulis",publishedDate:"November 20th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/8613.jpg",numberOfDownloads:13193,numberOfWosCitations:5,numberOfCrossrefCitations:11,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:19,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:35,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 10th 2018",dateEndSecondStepPublish:"July 31st 2018",dateEndThirdStepPublish:"September 29th 2018",dateEndFourthStepPublish:"December 18th 2018",dateEndFifthStepPublish:"February 16th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"9833",title:"Prof.",name:"George",middleName:null,surname:"Dekoulis",slug:"george-dekoulis",fullName:"George Dekoulis",profilePictureURL:"https://mts.intechopen.com/storage/users/9833/images/system/9833.jfif",biography:"Prof. George Dekoulis received his Ph.D. in Space Computing and Communications from Lancaster University, UK, in 2007. He was awarded a First Class BEng (Hons) degree in Communications Engineering from De Montfort University, UK, in 2001. He has received several awards from the Science and Technology Facilities Council (STFC), the Engineering and Physical Sciences Research Council (EPSRC), and the Hudswell International Research Scholarship (IET). He is the Founding Dean of the Faculty of Sciences and Technology at the American University of Cyprus (AUCY), Cyprus. He was previously a professor at the Aerospace Engineering Institute (AEI), Cyprus. Founder of the IEEE Aerospace and Electronic Systems Society (AESS), Cyprus. General chair of IEEE Aerospace Engineering Innovations 2019 (IEEE AEI 2019), Limassol, Cyprus. He has worked as a professor in Computer Science & Communications at various departments, such as Space & Planetary Physics, Aeronautical and Space Engineering, Professional Flight, Robotics/Mechatronics & Mechanical Engineering, Computer Science & Engineering, and Electrical and Electronics Engineering. His research focuses on the design of reconfigurable Digital Logic Computer Science and Engineering Systems.",institutionString:"American University of Cyprus (AUCY)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"9",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"111",title:"Aerospace Engineering",slug:"aerospace-engineering"}],chapters:[{id:"65403",title:"Green Comparable Alternatives of Hydrazines-Based Monopropellant and Bipropellant Rocket Systems",doi:"10.5772/intechopen.82676",slug:"green-comparable-alternatives-of-hydrazines-based-monopropellant-and-bipropellant-rocket-systems",totalDownloads:1639,totalCrossrefCites:1,totalDimensionsCites:4,hasAltmetrics:1,abstract:"Concepts are presented for “green” (with reduced hazards) replacements for monopropellant hydrazine propulsion systems and for hypergolic bipropellant systems while maintaining similar performance. At the onset of the “green propulsion” age, “green” alternatives to hydrazine propulsion have been emerging. The introduction rate of these into space systems is very slow due to the conservatism of the space propulsion industry. The concept presented here for monopropellant hydrazine systems offers gradual conversion to “green propellants” by dual capability of conventional hydrazine systems and ammonium dinitramide (ADN)-based systems. An initial risk reduction program has been carried out for materializing the concept. It includes proof of concept of dual use of all propulsion system parts. Materials compatibility and actual operation have been demonstrated. For bipropellants, we present the emerging “green” hypergolic system based on kerosene and peroxide, similar in performance to MMH/N2O4. Results of the proof-of-concept and development model systems are presented. The experimental results of various engine types demonstrate the capability to operate in both pulse and steady-state modes and the ability to produce different thrust levels. The fuel and oxidizer show very robust hypergolicity and short ignition delay times, as well as characteristic velocity efficiency exceeding 98%.",signatures:"Dov Hasan, Dan Grinstein, Alexander Kuznetsov, Benveniste Natan, Zohar Schlagman, Avihay Habibi and Moti Elyashiv",downloadPdfUrl:"/chapter/pdf-download/65403",previewPdfUrl:"/chapter/pdf-preview/65403",authors:[null],corrections:null},{id:"65003",title:"High Strain Rate Characterization of Thermoplastic Fiber-Reinforced Composites under Compressive Loading",doi:"10.5772/intechopen.82215",slug:"high-strain-rate-characterization-of-thermoplastic-fiber-reinforced-composites-under-compressive-loa",totalDownloads:1222,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Experimental study on the mechanical behavior of polyphenylene sulfide (PPS)-based composite laminates reinforced with carbon and glass fibers subjected to different strain rates under compression load is reported. Quasi-static tests have been carried out using an electromechanical universal testing machine at three different strain rates, while dynamic tests were done using a split-Hopkinson pressure bar (SHPB) apparatus at two pressure setups in the gas chamber. High-speed imaging system was used to monitor failure process during dynamic test, and these images were used to measure strain by digital image correlation (DIC) in order to compare the DIC-based measurements performed with the SPHPB strain gauges and quasi-static results. Fractography analysis was also performed to identify the main failure mechanisms induced at different strain rates.",signatures:"Carolina Ramirez, Vitor Reis, Carlos Opelt, Rafael Santiago, Facundo Almeraya, Mauricio V. Donadon, Citlalli Gaona, Rene Croche and Miguel Angel Baltazar",downloadPdfUrl:"/chapter/pdf-download/65003",previewPdfUrl:"/chapter/pdf-preview/65003",authors:[null],corrections:null},{id:"63682",title:"Matrix Converter for More Electric Aircraft",doi:"10.5772/intechopen.81056",slug:"matrix-converter-for-more-electric-aircraft",totalDownloads:1170,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"This proposed chapter discusses three methods that do not allow regenerative power from the matrix converter (MC) motor drive onto the aircraft power supply. According to aerospace power quality specifications, the regenerative power must be dissipated in the drive itself to avoid instability problem in aircraft power supply. These are bidirectional switch (BDS) method, input power clamp (IPC) method, and standard clamp circuit (SCC) method for aerospace applications. To identify regeneration in a matrix converter drive, two novel techniques are proposed. These are power comparison technique (PC) and input voltage reference technique (IVR). In both techniques, output power of MC and direction of speed, these factors are used to detect regeneration in MC drive. The electrical braking is important in many aerospace applications such as surface actuation and air-to-air (in-flight) refueling system. Therefore, the inherent regeneration capability of the matrix converter drive is not desirable for aerospace applications so it has to be avoided. The proposed methods are demonstrated through detailed simulation results and experimental verification. In order to prove the proposed methods with novel techniques, a 7.5-kW matrix converter fed 4-kW induction motor (IM) with inertial load has experimentally implemented. The obtained results using BDS method with PC technique proved avoiding regeneration with a matrix converter is feasible. This chapter is valuable for 150-kVA matrix converter for high-power application.",signatures:"Imayavaramban Munuswamy and Patrick W. Wheeler",downloadPdfUrl:"/chapter/pdf-download/63682",previewPdfUrl:"/chapter/pdf-preview/63682",authors:[null],corrections:null},{id:"64742",title:"Turbine Engine Lubricant and Additive Degradation Mechanisms",doi:"10.5772/intechopen.82398",slug:"turbine-engine-lubricant-and-additive-degradation-mechanisms",totalDownloads:1113,totalCrossrefCites:3,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Modern ester based synthetic lubricants have been used in various formulations with anti-oxidants, phosphorus based anti-wear additives and other additives for many years. The physical and chemical properties of both the basestock and additives are known to change through use. Basestocks are normally thought to degrade through various mechanisms, while additive can either degrade or are used as they react when they complete the function that they are added for. In this chapter, the composition of modern turbine engine lubricants and the mechanisms by which the lubricants degrade over time will be examined. Potential changes in bearing materials being evaluated for future engines and the effects of possible new ionic liquids based additives will be will be discussed as they relate to currently used additives. Also included will be a discussion of effects of degradation on the lubricant properties, how the changes affect turbine engines and how the changes can impact human health. These new materials introduce a number of new possible degradation schemes that must be evaluated before the materials enter wide-spread use.",signatures:"David W. Johnson",downloadPdfUrl:"/chapter/pdf-download/64742",previewPdfUrl:"/chapter/pdf-preview/64742",authors:[{id:"178441",title:"Dr.",name:"David",surname:"Johnson",slug:"david-johnson",fullName:"David Johnson"}],corrections:null},{id:"64957",title:"The Evolution of the Composite Fuselage: A Manufacturing Perspective",doi:"10.5772/intechopen.82353",slug:"the-evolution-of-the-composite-fuselage-a-manufacturing-perspective",totalDownloads:4151,totalCrossrefCites:3,totalDimensionsCites:5,hasAltmetrics:1,abstract:"A review of critical technologies and manufacturing advances that have enabled the evolution of the composite fuselage is described. The author’s perspective on several development, military, and production programs that have influenced and affected the current state of commercial fuselage production is presented. The enabling technologies and current approaches being used for wide body aircraft fuselage fabrication and the potential reasons why are addressed. Some questions about the future of composite fuselage are posed based on the lessons learned from today and yesterday.",signatures:"Alan Hiken",downloadPdfUrl:"/chapter/pdf-download/64957",previewPdfUrl:"/chapter/pdf-preview/64957",authors:[null],corrections:null},{id:"64528",title:"Robotic Autonomous Spacecraft Missions: Cassini Mission-To-Saturn Example",doi:"10.5772/intechopen.82161",slug:"robotic-autonomous-spacecraft-missions-cassini-mission-to-saturn-example",totalDownloads:982,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Robotic interplanetary spacecraft sent to the outer planets of our solar system face many challenges: maintaining internal health and functionality of spacecraft subsystems handling material stresses from solar heating close to Earth, the cold of deep space once the destination is reached, solar radiation and bombardment of cosmic rays; maintaining adequate power to support engineering devices and science instruments; handling time-critical onboard faults in the presence of the long round-trip light time; and preserving one-time “crucial event” activities such as moon/planet flybys, deployment of the probe, and selected science targets. As an example, this chapter details the strategy implemented on the Cassini Mission-to-Saturn spacecraft, how its onboard subsystems are protected and maintained, the advantage of automated onboard fault protection monitor/response routines, protocols implemented to preclude human error in uplinked sequences, and updating onboard flight software as new discoveries are uncovered about the adverse flight environment, so that mission objectives are met under the presence of an ever-increasing delay between ground issued commands and the Cassini spacecraft as it approaches the Saturnian system, safeguarding planetary protection constraints as the spacecraft was deposited into the planet in a final fiery plunge.",signatures:"Paula S. Morgan",downloadPdfUrl:"/chapter/pdf-download/64528",previewPdfUrl:"/chapter/pdf-preview/64528",authors:[{id:"110221",title:"Dr.",name:"Paula",surname:"Morgan",slug:"paula-morgan",fullName:"Paula Morgan"}],corrections:null},{id:"64840",title:"Advanced Nonlinear Modeling of Gas Turbine Dynamics",doi:"10.5772/intechopen.82015",slug:"advanced-nonlinear-modeling-of-gas-turbine-dynamics",totalDownloads:1340,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The process of gas turbine development requires different mathematical models. In particular, physics-based nonlinear dynamic models are widely used in the development of control and diagnostic systems. The present chapter firstly reviews known works on nonlinear dynamic engine modeling centering on model applications and developments. As an important development, modeling of heating up engine components is considered. This phenomenon consists in a radial clearance change during transients that influences engine static and dynamic performances. This clearance change is usually computed by a finite element method that is critical to computer resources. The chapter secondly presents a new and more rapid simulation methodology to integrate two dynamic processes, a general engine transient and a clearance change. This allows creating a more accurate and relatively fast engine dynamic model that is easy to use in the design of control and diagnostic systems. Finally, the chapter introduces further methodology enhancement consisting in the consideration of the influence of varying metal temperature on the strains induced by mechanical loads. To validate methodology, it is applied to a particular turbofan engine, and the simulated and real engine dynamic performances are compared.",signatures:"Roman L. Zelenskyi, Sergiy V. Yepifanov and Igor Loboda",downloadPdfUrl:"/chapter/pdf-download/64840",previewPdfUrl:"/chapter/pdf-preview/64840",authors:[null],corrections:null},{id:"63715",title:"Effect of Microstructure on Microhardness and Electrochemical Behavior in Hypereutectic Al-Fe Alloy Processed by Laser Surface Remelting",doi:"10.5772/intechopen.81095",slug:"effect-of-microstructure-on-microhardness-and-electrochemical-behavior-in-hypereutectic-al-fe-alloy-",totalDownloads:740,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"An analysis was made of microstructure of hypereutectic Al-2.0 wt.% Fe alloy treated by laser surface remelting (LSR), microhardness test, and electrochemical behavior test and their numerical simulation was done. Microstructure was analyzed by optical microscopy, field-emission scanning electron microscopy and Vickers microhardness tests. Results obtained in this study indicate in LSR-treatment occurred rapid heating and followed by rapid cooling, resulting in formation of a thin recast layer with a refined microstructure, with dissolution of precipitates and inclusions and formation of metastable phases, however, an overlapping line on consecutive weld fillets was observed. Furthermore, analysis of Vickers hardness were done in the cross-sectional area of treated sample and on the treated sample surface, therefore, result a greater microhardness of the treated region than untreated substrate. Through the electrochemical impedance spectroscopy (EIS) test, laser surface remelting-treated workpiece exhibit higher polarization resistance than untreated, at 11 times higher and capacitive behavior of material is related to aluminum oxide layer properties, then, microstructure characteristic caused by overlapping ratio and multi-track has a strong effect on electrochemical process.",signatures:"Moises Meza Pariona and Katieli Tives Micene",downloadPdfUrl:"/chapter/pdf-download/63715",previewPdfUrl:"/chapter/pdf-preview/63715",authors:[null],corrections:null},{id:"64541",title:"Optimal Control of Fuzzy Systems with Application to Rigid Body Attitude Control",doi:"10.5772/intechopen.82181",slug:"optimal-control-of-fuzzy-systems-with-application-to-rigid-body-attitude-control",totalDownloads:839,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"In this chapter, the author presents a theoretical result on the optimal control of nonlinear dynamic systems. In this theoretical result, the author presents the optimal control problem for nonlinear dynamic systems and shows that this problem can be solved by utilizing the dynamic programming approach and the inverse optimal approach. The author employs the dynamic programming approach to derive the Hamilton-Jacobi-Bellman (H-J-B) equation associated with the optimal control problem for nonlinear dynamic systems. Then, the author presents an analytic way to solve the H-J-B equation with the help of the inverse optimal approach. Based on the theoretical result presented in this chapter, the author establishes an optimal control design for TS-type fuzzy systems that guarantees the global asymptotic stability of an equilibrium point and the optimality with respect to a cost function and provides good convergence rates of state trajectories to an equilibrium point. The author considers the three-axis attitude stabilization problem of a rigid body to illustrate the optimal control design method for TS-type fuzzy systems. The author designs the optimal three-axis attitude stabilizing control law for a rigid body based on this optimal control design method and analyzes its control performance by numerical simulations.",signatures:"Yonmook Park",downloadPdfUrl:"/chapter/pdf-download/64541",previewPdfUrl:"/chapter/pdf-preview/64541",authors:[{id:"2861",title:"Dr.",name:"Yonmook",surname:"Park",slug:"yonmook-park",fullName:"Yonmook Park"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"6003",title:"Robotics",subtitle:"Legal, Ethical and Socioeconomic Impacts",isOpenForSubmission:!1,hash:"15ab11f5bb5aac89956dd8b42f261011",slug:"robotics-legal-ethical-and-socioeconomic-impacts",bookSignature:"George Dekoulis",coverURL:"https://cdn.intechopen.com/books/images_new/6003.jpg",editedByType:"Edited 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In this family, there are four types of viruses: α-coronavirus, β-coronavirus, γ-coronavirus, δ-coronavirus [1]. The CoV genome is an enveloped, positive-sense, and single-stranded RNA, and it has the largest genome of known RNA viruses. It is known that α- and β-CoV types cause infections in mammals as δ- and γ-CoVs infect birds [2]. Severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) belonging to β-CoVs are the most aggressive strains of coronaviruses and cause viral pneumonia outbreaks [3, 4]. SARS-CoV disease is a kind of pneumonia and caused by novel CoV whose genome structure was more than 82% identical to those of SARS-CoV, named coronavirus disease 2019 (COVID-19) [5, 6]. SARS-Cov-2 is a beta gene virus genetically very close to bat-CoVRaTG13, and bat-SL-CoVZC45 Covs can cause severe illness. As the COVID-19 outbreak turned into a global threat, the World Health Organization (WHO) announced it as a global pandemic on 12 March 2020. The COVID-19 pandemic has changed the scenario of the entire world. COVID-19 outbreak started in Wuhan, China, has globally spread to 219 countries and territories [7]. Currently, there are few vaccines for COVID-19. Their acceptance and efficacy are an issue of debate across the whole world. Therefore, there is an urgent need to find drugs or vaccines for the treatment of COVID-19 infections effectively. However, there are some studies related to the use of known drugs such as remdesivir and chloroquine that have proved efficacy on COVID-19 infection. We summarize some antiviral drugs as therapeutic options for the treatment of COVID-19 [8].
COVID-19 mainly attacks the respiratory-tract-associated organs. Additionally, the virus has shown impact various to other organs or systems such as the gastrointestinal system, nervous system, etc. [9]. The most common symptoms in COVID-19 patients are fever, dry cough, loss of taste, lethargy, shortness of breath, dyspnea, chest pain, fatigue, myalgia, whereas headache, dizziness, abdominal pain, diarrhea, nausea, and vomiting are less commonly observed [10, 11]. Anosmia is also one of the most critical symptoms in COVID-19 patients [12]. COVID-19 is more contagious than other coronaviruses, and its transmission rate is higher than the closely related strain, SARS-CoV-10 [13]. Currently, new variants of COVID-19 are reported from different regions of the world. Coronavirus interacts with cell surface receptors such as angiotensin-converting enzyme-2 (ACE-2) and neuropilin to gain entry inside the cell. The receptor-binding domain of viral spike protein is essential in SARS-CoV-2 entry into the host cell via surface ACE-2 [14]. Recently, another cell receptor Neuropilin-1 was found to be involved in SARS-CoV-2 entry. After binding to the receptor, the conformational change in the spike protein leads to virus fusion with the host cell membrane. The virus may transfer the RNA directly inside the cells or may proceed through the endosomal pathway [15]. Upon translation of viral RNA, the viral replicase polyprotein PP1a and PP1ab are produced and cleaved into small products by viral endopeptidase [16]. RNA-dependent RNA polymerase (RdRp) produces subgenomic RNAs by discontinuous transcription [16, 17]. This further gets translated into respective viral proteins. After processing through the endoplasmic reticulum (ER), ER-Golgi intermediate compartment (ERGIC), and Golgi complex, the viral RNA and proteins are assembled into virions. These virions are transported through vesicles and exocytosed for transmission. These steps of the viral life cycle are beneficial virus inhibition targets for different drugs. The coronaviruses are ribonucleic acid (RNA) viruses, which have a positive single-strand RNA [14, 18]. When SARS-CoV-2 enters the body and comes in contact with the host cell membrane, some changes occur in the structure of the virus. The human TMPRSS2 protein alters the conformation of the spike glycoprotein in the virus. Two substantial protease enzymes, 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLPro), have essential roles in its viral replication process after it enters the host cell via ACE2 receptors [19]. The expression of several genes, such as AHCYL2, ZNF385B, etc., appears to have a strong correlation with the expression of ACE2 and TMPRSS2 protein receptors in human healthy and normal lung cells [20].
However, repurposing drugs could prove to be beneficial tactics for finding COVID-19 treatment, including cost-effectiveness, elimination of some clinical trial steps, faster on-field availability, combining the drugs with other possible drugs, and the invention of information about the mechanisms of the existing drug. Researchers were able to develop the possible COVID-19 medications using information from previous CoVs therapies, genetic sequences, and protein modeling studies. Antimalarials, antivirals, antibiotics, and corticosteroids are among the most often studied medications, and they have been repurposed based on their ability to neutralize viruses, reduce lung inflammation, or alleviate other illness symptoms. Chloroquine (CQ), hydroxychloroquine (HCQ), and azithromycin (AZM) are the most often utilized antiviral drugs against COVID-19, since they have already demonstrated reasonable antiviral efficacy against SARS-CoV, MERS-CoV, and SARS-CoV-2. Anti-HIV medications lopinavir/ritonavir (LPV/RTV) are being studied for COVID-19 since they were successful in previous CoV epidemics. Furthermore, the anti-Ebola medicine remdesivir (RDV) was evaluated for COVID-19 and garnered further attention.
Similarly, favipiravir (FPV), ribavirin (RBV), umifenovir (UFV), and oseltamivir (OTV) have broad-spectrum antiviral activities and clinically tested against COVID-19. The effective uses of HCQ, RDV, LPV/RTV, or LPV/RTV in combination with Interferon (IFN) β-1a against COVID-19 [21], all these drugs had little or no effect on overall mortality, initiation of ventilation, and duration of hospital stay in hospitalized patients. So far, to treat severe and critical COVID-19, only corticosteroids have proven effective [21]. Other drugs, such as Angiotensin-Converting-Enzyme inhibitors (ACEi), have also been used to treat COVID-19. However, no clear correlation was reported between mortality rate and ACEi drugs in hypertension patients with COVID-19 [22]. Due to the possibility of secondary infection in these patients, antibiotics have been used as various protocols [23].
Umifenovir (UFV) may interact with SARS-CoV-2 surface glycoproteins and lipids and obstruct the interaction with the entry receptor ACE-2. Antibodies against SARS-CoV-2 may prevent the virus from entering the body and causing illness. Chloroquine (CQ), hydroxychloroquine (HCQ), and azithromycin (AZM) can raise endosomal pH, making viral entrance and RNA release more difficult. CQ, HCQ, and AZM all have immunomodulatory properties. RDV, FPV, and RBV are nucleoside inhibitors that impede RNA replication and reduce RNA-dependent RNA polymerase activity. Fraternization of LPV with viral protease may change proteolysis. OTV may interact with components involved in exocytosis, preventing the virus from leaving the cell. Antibodies against cytokine receptors and corticosteroids have been shown to have anti-inflammatory properties in the face of excessive immune responses. Drugs such as CQ are wide-spectrum inhibitors of viral cell entry, and RDV is a wide-spectrum RNA polymerase inhibitor. SARS-CoV-2 infection concurrently triggers the host immune system and an inflammatory cascade response (cytokine storm). These are being targeted in the treatment of COVID-19 patients [23].
So far, no fully effective drug has been discovered against this virus. The antiviral drugs, usually nucleoside analogs or intracellular proteases, block the virus by preventing its entry into the cell or by interfering with its replication inside the cell. Protease inhibitors target certain proteases, whereas fusion inhibitors block the fusion phase of viral entrance. Transcription inhibitors impede viral replication by inhibiting RNA-dependent RNA polymerase during the reverse transcription process. Nucleoside reverse transcriptases are some of the transcriptase inhibitors. M2 channel protein is a target for certain antivirals. In this chapter, we have provided information about repurposed drugs that are used against COVID-19, the mechanism of activity, therapeutic regimens, pharmacokinetics, and drug-drug interactions [7, 8].
The rationale major biochemical events and components in the replication cycle of coronavirus are considered as targets for currently developed drugs. These include the spike protein, proteolytic enzymes, and RNA-dependent RNA polymerase [24]. SARS-CoV-2 is transmitted mainly via respiratory droplets. The virus enters the host cells through two pathways, either via endosomes or plasma membrane fusion. In both mechanisms, the viral S protein mediates attachment to the membrane of the host cell and engages ACE2 as the entry receptor [25]. A host protease termed transmembrane serine protease 2 (TMPRSS2) activates the connection between S protein and ACE-2 [26]. S protein is used by the virus to destroy antibodies and make it simpler for it to attach to host receptors [27]. Beta-coronaviruses generally employ hemagglutinin-esterase (HE) to bind to sialic acid on the glycoprotein surface, despite the fact that the fusion machinery of SARS-CoV-2 remains unknown [28]. Fusion inhibitors might be used to prevent these fusion stages.
The envelope is peeled off when fusion is complete, and the SARS-CoV-2 genome, together with its nucleocapsid, penetrates the cytoplasm of the host cell. Its genome comprises the open reading frames 1a and 1b (ORF1a and ORF1b) genes, which create two polyproteins (pp) named pp1a and pp1b, which aid in the viral translation process by hijacking host ribosomes [29]. Main protease (Mpro) and papain-like protease (Ppro) break these polyproteins to create multiple non-structural proteins [30]. Aside from Mpro and Ppro, SARS-CoV-2 has 3C-like cysteine protease (3CLPro), which has a 96% resemblance to SARS-CoV. These proteases are essential for viral replication and transcription, and protease inhibitors inhibiting these proteases are potential antivirals for SARS-CoV-2. The promising clinical outcomes for COVID-19 patients should be obtained by using alpha-interferon, chloroquine phosphate, arabinol, remdesivir, lopinavir/ritonavir, and anti-inflammatory drugs [31, 32, 33, 34]. Moreover, clinical trials with these drugs should be performed on COVID-19 patients to prove their efficacy and safety as proposed for tocilizumab (Figure 1) [35].
Schematic diagram of the life cycle of SARS-CoV-2.
Highest sequence similarity (~96%) was observed for the bat Coronavirus. So, it has been speculated that COVID-19 was transmitted from bats to humans. The intermediary animal host could be a pangolin or dog. COVID-19 illness is spread via intimate contact with an infected individual, as well as minute respiratory droplets emitted during coughing, sneezing, or talking [36]. Small droplets of saliva or sputum emitted from the mouth might carry large amounts of viruses that can linger in the air for lengthy periods of time and function as infection carriers. Even when a person is not in direct physical touch with the infected individual, inhaling these minute droplets causes viral infection to move from the sick to the healthy. The virus enters the human body via the eyes, nose, and mouth and spreads by encountering the virus on infected surfaces and then touching these bodily areas [37]. Environmental factors such as temperature and humidity influence viral propagation across infected surfaces [38]. The binding of homotrimer spike protein (S) on the virus’s surface to ACE2 on the host’s cell membrane facilitates SARS-CoV-2 entry into host cells [16]. The host cell receptor’s credit is a critical predictor of the virus’s tissue tropism and pathogenicity. The life cycle of SARS-CoV-2 is similar to the SARS-CoV and MERS-CoV [39]. Different strategies have been adopted to fight COVID-19.
COVID-19 diagnosis is a crucial step in tracking the virus and understanding its spread. This aids in the prevention of transmission as well as adequate patient care. COVID-19 is diagnosed in the first instance by observing signs and symptoms such as first loss of smell or taste or both, cough, mild to high fever, myalgia or weariness, and so on [40]. In addition, some people experience gastrointestinal problems such as vomiting, diarrhea, and nausea [41]. However, variations in the development of symptoms ranging from asymptomatic to severe instances, such as septic shock, metabolic acidosis, coagulation malfunction, and acute respiratory pneumonia-like syndrome, have been recorded often [17]. These indications and symptoms should only be used as a starting point for additional testing, not as a diagnostic tool. The recognition of symptoms in clinical conditions is the most important factor in diagnosis. Swabs are used to obtain pathological samples from the upper and lower respiratory areas (throat, oropharyngeal, nasopharyngeal, broncho-alveolar fluid, and sputum). The virus is still absent in the blood and urine of infected people, hence they are not regarded valid clinical specimens. The interlink between the temporal surge of viral load and its bio-distribution in different tissues of the body has a critical implication on the accuracy of various tests for diagnosis, according to reports of inconsistency in RTPCR test results for CoV-SARS-2 in various tissues [42] and temporal variation of test results from the same tissues [43]. SARS-spike CoV-2’s surface glycoprotein binds to the ACE2 receptor and then enters the host cell. Viral particles release their DNA after entering the host cell, which is then translated into protein, and additional viral particles are created, which are then released to infect the next cells. Many assays (molecular and immunological assays) or tools have been used for the diagnosis of COVID-19 and many more are currently in development.
SARS-Cov-2 infections currently have no vaccinations or antiviral therapies available [44]. Because developing safe and stable vaccines takes time and the pandemic is still going on, it’s critical to test and discover current medications that are already effective against SARS and MERS to determine whether they can be effectively applied to SARSCov-2. Various preclinical studies on other CoVs genetically very close to SARS-Cov-2 suggested that promising clinical outcomes for COVID-19 patients should be obtained by using several drugs including alpha-interferon, chloroquine phosphate, arabinol, remdesivir, lopinavir/ritonavir, and anti-inflammatory drugs. In a large-scale drug screening, nelfinavir has potent antiviral activity against SARS-Cov-2 [45]. Besides, praziquantel, pitavastatin, and perampanel might be effective against SARS-CoV-2. The outbreak of COVID-19 infection is related to the unavailability of specific drugs to combat this viral infection. Despite the challenges related to COVID-19 therapy, there are still several approaches being undertaken that show significant outcomes [5]. Discuss the positive impacts of some of the clinically used drugs for the COVID-19. Some drugs are in clinical trials, and some have shown significant promise in COVID-19 patients [46]. To find the solutions for COVID-19, great efforts have been made and are continued to develop vaccines, small-molecule drugs, or monoclonal antibodies that can prevent the infection [47]. In addition to drugs under clinical trials, some vaccines are expected to play a significant role in controlling the COVID-19 pandemic (Figure 2).
Common inhibitory action of antiviral drugs.
In 2009, Gilead Sciences, Inc. (USA) developed an antiviral drug called Remdesivir (RDV) to treat hepatitis B [48]. It did not indicate a desirable act against hepatitis. However, it is effective against other viruses, such as the Nipah virus, hepatitis C, and Marburg [49]. RDV is a broad-spectrum antiviral nucleoside analog, and now it is used as a treatment option for COVID-19 [50]. It is the class of polymerase inhibitors and showed activity against different RNA viruses, including SARS-CoV, MERS-CoV, Lassa fever virus, Junin virus, respiratory syncytial virus, Nipah virus, Hendra viruses, filoviruses, and Ebola viruses. RDV is a prodrug of its parent adenosine triphosphate analog, (2R,3R,4S,5R)-2-(4-aminopyrrolo(2,1-f)(1,2,4)triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)oxolane-2-carbonitrile (GS-441524), and has similarity to the adenine nucleic acid structurally. Both of these drugs are metabolized into the active component as nucleoside triphosphate (GS-443902) after ingestion and show antiviral activity against SARS-CoV [51]. RDV targets the viral genome replication process by acting as an RdRp inhibitor [52], RDV was used to block the RNA-dependent RNA polymerase of SARS-CoV-2. On metabolization of RDV into active nucleoside triphosphate (NTP), which competes with ATP for incorporation into nascent RNA strands, premature RNA synthesis occurs, resulting in RNA strand termination and cessation of growth [51]. RDV when tested through in vitro studies using the Vero E6 cells showed an EC50 value of 1.76 μM that showed its activity against SARS-CoV-2 [53]. Intravenous remdesivir treatment showed significant improvement for COVID-19. RDV and chloroquine are highly effective in the control of SARS-CoV-2 infection. In severe COVID-19 treated with RDV, improvements in the clinical finding were observed in 68% of patients [54]. However, in October 2020, the WHO removed it from the list of effective drugs in the treatment procedure of COVID-19 patients because it failed in the first trials for the treatment of COVID-19 [42]. There are still controversies regarding the results, no benefit in COVID-19 treatment using RDV; whereas, the company claims it as a promising drug for the same. After penetrating the cell, RDV as a prodrug (GS-5734) and like Favipiravir, binds to the triphosphate group under esterase, kinase, and phosphatase enzymatic reactions. These enzymes modify the structure of RDV and convert it to the active form, RDV-triphosphate (RDV-TP or GS-441524) [55]. After virus entry into the cell cytoplasm, this prodrug gets activated and loses its ability to diffuse to the intercellular space [53]. However, the primary mechanism of action of RDV against SARS-CoV-2 is unclear, and more research is necessary to understand it [56]. In an in vitro study, the combination of RDV and chloroquine (antimalarial drug) effectively inhibited SARS-CoV-2 growth in Vero E6 cells [19]. RDV is used to treat COVID-19 cases.
The combined use of RDV and IFN-β created a higher antiviral activity compared with the lopinavir/ritonavir-IFN-β combination against the MERS-CoV virus. Additionally, RDV could be better pulmonary function, cause fall lung viral loads and severe lung pathology in mice; on the contrary, lopinavir/ritonavir-IFN-β could not [57]. In two clinical studies, the use of RDV has been carried out against severe or mild respiratory infections caused by COVID-19. Recently, RDV for emergency use to treat COVID-19, including five antiviral drugs, ribavirin, RDV, sofosbuvir, galidesivir, and tenofovir, was conducted against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp); these drugs showed promising results against COVID-19. Prominent adverse reactions were an acute respiratory failure, decreased glomerular filtration rate, lymphocytopenia, pyrexia, hyperglycemia, increased anemia, increased creatine, and liver transaminases. RDV given in combination with baricitinib (Janus kinase inhibitor used to hinder intracellular signaling of cytokines) was effective compared with RDV alone in terms of reducing recovery time additionally speeding improvement. RDV’s parent nucleotide GS-441524 is superior and less toxic than its prodrug form and has shown efficacy [58].
Favipiravir (Avigan or T705) is a synthetic antiviral agent that was first marketed as an anti-influenza drug in Japan. It is a derivative of pyrazine carboxamide (6-fluoro-3-hydroxy-2-pyrazine carboxamide) [59]. Due to its similarity to the purine (guanine) nucleotide, it is a type of RNA-dependent RNA-polymerase (RdRp) inhibitor. RdRp uses Favipiravir-RTP in the synthesis of mRNA strands, which can consequently stop viral protein synthesis via suppressing the translation process. Activated Favipiravir-RTP could suppress the SARS-CoV-2 RdRp enzyme and inhibit viral mRNA elongation and protein synthesis [60]. Favipiravir acts against RNA viruses by working on viral genetic copying to prevent its reproduction. A phase 3 clinical trial was involved for the treatment of COVID-19 disease using Favipiravir. For the first day, take 1800 mg twice a day, then 600 mg three times a day from the second day onward for a total of 14 days. Normalization of pyrexia, respiratory rate, and cough alleviation for at least 72 h are the key objectives [61]. The precursor of this drug known as T1105 has anti-influenza effects [62]. Drug excretion is through renal elimination and is mainly impacted by aldehyde oxidase and xanthine oxidase [62]. Favipiravir is a prodrug that is phosphorylated upon its entry into the cell and converted to an active antiviral form, favipiravir ibufuranosyl-5′-triphosphate (T-705-RTP). Favipiravir was first prescribed in Wuhan, to treat patients with SARS-CoV-2 infection. In June 2020, it was approved for mild-to-moderate COVID-19 cases in India. Favipiravir has been consumed to cure distinct viral diseases. Favipiravir was effective against some RNA viruses, such as yellow fever virus, Lisa virus, West Nile virus, Bunyavirus, arenavirus, flavivirus, filoviruses, and Ebola virus [63]. The exact mechanism of action is not clear against SARS-CoV-2. Favipiravir is considered a potential drug for COVID-19 and is currently used for COVID-19 treatment in Japan and Indonesia. Besides, its anti-influenza virus action, it stops the replication of RNA viruses such as flavi-, alpha-, filo-, bunya-, arena-, noroviruses [64]. Favipiravir showed a more powerful antiviral activity than lopinavir/ritonavir. Adverse reactions are not observed in a favipiravir therapy group. Compared with the lopinavir/ritonavir group, it had considerably fewer adverse effects. In a Japanese study, FPV was also shown to control inflammatory mediators and pneumonia progression in COVID-19 patients [65]. Severe or critical COVID-19 patients showed improvements after treating with FPV and FPV also led to improved lung histology [66].
Lopinavir is an antiviral drug belonging to the family of protease inhibitors. It is commonly used to treat Acquired Immunodeficiency Syndrome (AIDS) and prevent HIV from spreading inside the body. Lopinavir/ritonavir (LPV/RTV) is used in combination with other antiretroviral drugs for the treatment of HIV-1 infection. In the coronavirus pandemic, when no definitive drug was proposed to treat patients, it was used in combination with Ritonavir. This LPV/RTV is branded as Kaletra. Lopinavir has a relatively short half-life in the blood and is affected by the cytochrome p450 enzyme, while Ritonavir is a protease inhibitor and reduces the Lopinavir metabolism by suppressing the function of cytochrome p450. The half-life of Lopinavir is improved, and its circulation period is increased. LPV/RTV acts as a protease inhibitor drug and inhibits the action of 3-CLpro, a chymotrypsin-like protease enzyme, that plays a vital role in the processing and interferes with the process of viral replication and its release from host cells [67, 68, 69]. LPV/RTV use is related to diverse side effects, mainly in the gastrointestinal tract. Diarrhea, impaired hepatic cell function, and pancreatitis are some of these crucial side effects.
The use of lopinavir as an emergency drug in China increased the eosinophil count among COVID-19 patients [70]. In an in silico study, LPV/RTV used as HIV protease inhibitors inhibited the main protease (MPro) of SARS-CoV-2 [71]. The LPV/RTV is being used as an emergency treatment for COVID-19 patients in some countries [72]. LPV/RTV alone or in combination with interferon (INF)-β, an inflammation regulator, has been listed by WHO as options for “solidarity” clinical trial for COVID-19. COVID-19 might benefit from LPV/RTV since it reduces viral load and improves clinical symptoms. Lung damage was also significantly reduced when LPV/RTV and umifenovir were used together [73]. A research found that while LPV/RTV therapy was associated with a better result, it did not significantly speed up the clinical progression of severe COVID-19 infection. Although the efficacy of lopinavir for COVID-19 has yet to be determined, LPV/RTV has been employed in the treatment of COVID-19 patients [57]. Now, LPV/RTV and IFN-β1b are in phase 2 for the MERS therapy. Despite the positive findings, in a recent study performed on patients with SARS-CoV-2 infection, the LPV/RTV did not provide clinical improvement compared with standard care processes [72]. Findings of LPV/RTV clinical efficacy remain limited and primarily anecdotal cases. LPV/RTV in the therapy of COVID-19 is needed as current results contradict. LPV/RTV can ameliorate the outcome of MERS-CoV infection [74]. Moreover, LPV/RTV is assumed as a therapeutic option for COVID-19 pneumonia [72]. Thus, more well-designed clinical studies are necessary to identify their efficacy as therapeutic agents for COVID-19.
Novaferon has potential as an antiviral drug against COVID-19. It is a synthesized protein consisting of 167 amino acids, designed on the technical basis of DNA shuffling technology. The antiviral effects of novaferon are shown alone and in combination with lopinavir/ritonavir (LPV/RTV) for COVID-19 treatment. Novaferon inhibited the viral replication in infected cells (EC50 = 1.02 ng/ml) and protected healthy cells from SARS-CoV-2 infection (EC50 = 0.1 ng/ml). Both novaferon and novaferon plus LPV/RTV groups had significantly higher SARS-CoV-2 clearance rates on day 6 than the LPV/RTV group [8].
Ribavirin (Virazole) is an antiviral drug belonging to the nucleoside analogues, (1-beta-d-ribofuranosyl-1,2,4-triazole-3-carboxamide). It is a synthetic nucleoside analog with a guanosine-like structure. Ribavirin disrupts viral DNA and RNA replication, thereby inhibiting virus proliferation in the cell. Although Ribavirin’s primary mechanism of action is suppressing the virus replication, and can also interfere with viral RNA capping, which depends on the presence of natural guanosine in the RNA structure. The natural guanosine in the viral RNA structure prevents the breakdown of RNA strands. Ribavirin reduces the guanosine synthesis in the cell by inhibiting the activity of the inosine monophosphate dehydrogenase enzyme, which negatively impacts virus replication [75]. Although Virazole does not entirely inhibit viral RNA synthesis, the synthesis of the viral genetic material is severely impaired. It results in significant and persistent mutations in viral RNA, which reduce the viability of the virus in host cells [76]. Besides, the presence of Ribavirin in the patient’s body can reduce viral immune evasion and boost immune maintenance [77]. It is the first broad-spectrum antiviral drug against DNA and RNA viruses [75]. It is used clinically to treat HIV and hepatitis C virus (HCV) patients.
Ribavirin, which has been studied for its antiviral effectiveness against SARS-CoV-2, is used to inhibit viral RNA production and viral mRNA capping with a broad range of antiviral activity. It’s a prodrug that, when metabolized, looks like purine RNA nucleotide, which prevents viral multiplication by interfering with RNA metabolism. It was discovered in a comparison study of SARS-CoV-2 patients treated with lopinavir/ritonavir (LPV/RTV) and ribavirin combination treatment [77]. Ribavirin is one of the medications used to treat COVID-19 in conjunction with either IFN alpha or LPV/RTV [46]. Using ribavirin in combination with sofosbuvir and remdesivir, docking and modeling studies revealed that ribavirin is a viable candidate medication for COVID-19 therapy [78]. Ribavirin and sofosbuvir are currently part of the therapeutic regimen to treat COVID-19 in some countries.
Ribavirin inhibits the function of inosine monophosphate dehydrogenase, which affects the formation of guanosine triphosphate (GTP), preventing RNA and DNA viral replication. During the SARS outbreak in Hong Kong, ribavirin was utilized. With or without steroids, it was occasionally chosen. The combination of ribavirin and interferon-β, which appears to inhibit SARS-CoV replication, has shown significant efficacy in the inhibition of SARS-CoV [79]. The ribavirin triple antiviral treatment was safe and superior compared with lopinavir-ritonavir combined therapy.
The drug showed antiviral efficacy against canine distemper virus, hepatitis C virus, Enterovirus, Chikungunya virus, and Semliki Forest virus, orthopoxvirus, influenza virus, flavi- and paramyxoviruses [80]. A study observed reduced replication of the MERS-CoV in rhesus macaques upon treatment with IFN-α2b and RBV [81]. RBV in combination with LPV/RTV was used in SARS-CoV and MERS-CoV trials [82]. In the case of SARS-CoV-2 infection, an in vitro study showed the EC50 of RBV as 109.50 uM [31]. A study included RBV along with LPV/RTV and IFN-α in the treatment of hospitalized COVID-19 patients. When compared with those that only received LPV-RTV, the triple treatment was found to be effective in reducing illness symptoms and viral shedding. The RBV dosage was 400 mg bid for 14 days, paired with 400 mg/100 mg of LPV/RTV + IFN-β. A research examined the effectiveness of antivirals sofosbuvir/daclatasvir and RBV in the treatment of COVID-19 patients. COVID-19 patients treated with RBV had a greater death rate (33%) than those treated with sofosbuvir/daclatasvir. A cohort study comparing RBV vs. supportive therapy stated that RBV did not help in reducing the mortality rate in COVID-19 patients [83].
It is an antiviral widely used to treat the influenza virus. Arbidol can prevent SARS-CoV-2 infection
Darunavir, an anti-HIV drug, is recommended for COVID-19 treatment in Italy. It is used in a combined regimen along with cytochrome P-450 inhibitors such as ritonavir or cobicistat and confirmed their replication inhibitory effect against SARS-CoV-2. A clinical trial assessed the effectiveness of darunavir combination with other antivirals and hydroxychloroquine for COVID-19 patients. A combination of darunavir and cobicistat is also being tested [93]. PREZCOBIX®, a fixed-dose combination of darunavir and cobicistat, is also used to treat COVID-19. COVID-19 infection was recently discovered in HIV-positive individuals who were already taking darunavir, raising questions about the effectiveness of this HIV protease inhibitor. The darunavir might not be effective in preventing SARS-CoV-2 infection at the dosage of 800 mg [94]. Darunavir is a second generation of HIV-1 protease inhibitors used to prevent SARS-CoV-2 infection in vitro [17] by inhibiting viral replication at 300 μM, and this inhibition efficiency was 280-fold compared with the untreated groups. Darunavir boosted with ritonavir or cobicistat is used in HIV/AIDS treatment. The efficacy of darunavir or ritonavir is enhanced by cytochrome p450 (CYP3A) inhibition [95]. Cell experiments with darunavir showed that the drug inhibited viral replication of COVID-19 in vitro. The lopinavir/ritonavir used in the treatment of HIV/AIDS has more efficacy and tolerability than darunavir, its use in COVID-19 is limited.
Oseltamivir (Tamiflu) is an antiviral agent that is used for patients with influenza A and B. It is a protease inhibitor, which specifically inhibits the neuraminidase enzyme in the influenza virus. This enzyme has a key role in the binding of the influenza virus to the cell membrane and spread throughout the body. Therefore, Oseltamivir, by targeting neuraminidase, prevents the spread of the influenza virus and its progression inside the body [96]. This drug was used in the treatment of COVID-19 infection, which showed an appropriate effect on patients [41]. Oseltamivir has been applied in concomitant regimens with other drugs such as Hydroxychloroquine or Favipiravirs [97]. In addition to treating influenza A and B patients, this drug may also be used in severe cases. For the treatment of flu patients, Tamiflu is prescribed in a 75 mg dosage twice a day and once a day as prophylaxis. The main side effects of this drug can be nausea and headache [98]. Neuraminidase inhibitors seem beneficial for COVID-19 patients and can reduce their ventilator requirements [99]. The precise mechanism of action of Oseltamivir against COVID-19 infection is still unclear. Oseltamivir is a synthetic derivative prodrug of ethyl ester [100]. It acts as a neuraminidase inhibitor against the influenza virus and is also effective for various avian influenza virus strains [101]. An in vitro oseltamivir study on H5N1 influenza showed that the IC50 was 0.1–4.9 nM [102]. In vivo study involving H5N1 infection required a longer course and higher dosage of Oseltamivir. The COVID-19 originated in China during flu season, and hence earlier, many patients received oseltamivir treatment until the causative agent SARSCoV-2 was discovered. Some current clinical trials have used oseltamivir in combination with other major therapeutic drugs [31, 41].
Sofosbuvir is an antiviral drug and RdRp inhibitor that exerts its effect by suppressing RdRp enzyme activity. A combination of Sofosbuvir with Ledipasvir is used for treating patients with genotype 1 of HCV67. Because of the similarity in the transcription and replication mechanism of the SARS-CoV-2 with HCV in host cells, physicians speculate that this drug may help treat COVID-19 patients [103]. This drug disrupts the activity of RdRp by acting like free nucleotides that are essential for viral mRNA synthesis [104]. Sofosbuvir is a potential option for COVID-19 treatment [105], and extensive clinical studies should be performed to verify the effectiveness of this drug.
Danoprevir, an HCV N53 protease inhibitor, is authorized in China for the treatment of noncirrhotic genotype 1b chronic hepatitis C in combination with other medications. In China, only two clinical studies of danoprevir coupled with ritonavir in the treatment of SARS-CoV-2 infection were completed [8].
In a computer simulation, atazanavir bonded more firmly to the active site of SARS-CoV-2 MPro than lopinavir, and atazanavir suppressed SARS-CoV-2 replication in a test tube. A prior trial on HIV-positive individuals found that combining atazanavir with ritonavir enhanced glucose uptake and lipid parameters while also lowering fasting glucose levels more efficiently than lopinavir-ritonavir. The atazanavir might be an alternative for lopinavir when combined with ritonavir for COVID-19 treatment. This antiviral drug is an option for COVID-19 treatment [8].
SARS-CoV-2 penetrates host cells by receptor-mediated endocytosis, just as other viruses. AP2-related protein kinase 1 controls the process of endocytosis (AAK1). As a result, disrupting AAK1 will prevent not just viral entrance but also intracellular viral assembly. Baricitinib is a Janus kinase (JAK) inhibitor that has a high affinity for AAK1 and can inhibit it. SARS-CoV-2 infection can be treated with baricitinib, which inhibits both viral entry and the inflammatory response [106]. JAK inhibitors such as ruxolitinib and fedratinib, which are linked to baricitinib, decreased clathrin-mediated endocytosis at higher dosages, suggesting that they may not be effective at acceptable concentrations in lowering viral infectivity. Neutropenia, lymphocytopenia, and viral reactivation have all been linked to the use of baricitinib for therapeutic purposes. Because individuals infected with SARSCoV-2 had a lower absolute lymphocyte count, baricitinib may increase the risk of co-infection [107].
Blocking virus-host fusion is a promising target for the novel antiviral agents that inhibit the Abl kinase pathway [41]. In a study, imatinib, an Abl kinase inhibitor, was observed to block the replication of SARS and MERS viruses by blocking viral fusion in 2016 [108]. COVID-19 utilized the SARS-coronavirus receptor ACE2 as well as the cellular protease TMPRSS2 to get access to target cells; therefore, TMPRSS2, transmembrane serine protease 2, inhibiting medicines such imatinib might be evaluated as COVID-19 disease treatment alternatives [37].
Another possible medicine that targets the fusion stage in viruses is camostat mesylate, a serine protease inhibitor. SARS-CoV-2 enters target host cells via ACE-2 receptors and/or TMPRSS2 receptors, with camostat mesylate acting as a TMPRSS2 inhibitor. It inhibits the virus’s cellular entrance by downregulating the production of the SARS-CoV-2 spike (S) protein, which prevents surface fusion. SARS-CoV infection in human bronchial epithelial cells was inhibited by camostat mesylate [109]. In vitro testing revealed that camostat mesylate and E-64d (a cysteine protease inhibitor) effectively blocked SARS-CoV-2 TMPRSS2 binding. Clinical studies are now underway to compare the efficacy of hydroxychloroquine and camostat mesylate vs. hydroxychloroquine alone. Another serine protease inhibitor, nafamostat mesylate, was shown to be 15 times more effective in preventing the SARS-CoV-2 virus from infecting host cells. As a result, nafamostat mesylate can be regarded a preferable option to camostat mesylate due to its more robust antiviral activity and acceptable safety profile [37]. Disseminated intravascular coagulation is also treated with nafamostat mesylate (DIC). It will aid in the management of DIC, as seen by increased fibrinolysis in COVID-19 patients [110].
In an in vitro research utilizing Vero E6 cells, nitazoxanide and its active component, tizoxanide, showed promise against MERS CoV and SARS CoV-2, with EC50 values of 0.92 and 2.12 μM, respectively [111]. In addition to coronaviruses, it exhibited action against norovirus, rotavirus, parainfluenza, respiratory syncytial virus, and influenza virus. This antiviral efficacy is due to the fact that the action mechanism is based on interfering with the virus’s host-regulated reproduction pathways rather than the virus’s particular pathways [112]. Nitazoxanide stimulates innate antiviral systems through amplification of cytoplasmic RNA sensing and type 1 IFN pathways. Nitazoxanide increases the expression of certain host systems that interfere with viral infection, allowing viruses to evade the host’s cellular defenses [113]. The nitazoxanide used against influenza viruses blocks the maturation of viral hemagglutinin at the post-translational stage [112]. Even if the findings aren’t promising, this medicine is used to treat some acute respiratory infections such as influenza. Although the in vitro activity of nitazoxanide against SARS-CoV-2 is promising, additional research is needed to understand its function in the management of COVID-19 (Figure 3).
Chemical structure of antiviral drugs.
Other various antiviral agents have been utilized to determine their impacts against SARS-CoV-2. Galidesivir is a nucleoside analog and a protease inhibitor [114]. This drug mechanism on COVID-19 is hypothesized to be similar to other antivirals, although its exact action mechanism is unknown. Another antiviral agent for COVID-19 is Tenofovir, which is known as an anti-influenza drug. It is an antiretroviral agent that targets DNA polymerase and inhibits virus replication [115, 116]. The action mechanism of this substance against COVID-19 requires further studies.
A fusion inhibitor is a group of antivirals that inhibit the fusion process during viral entry into the host cells. Some drugs are available with umifenovir and camostat mesylate representing antiviral activity against SARS-CoV-2 [117].
Some protease inhibitors such as lopinavir, darunavir, and atazanavir are used against COVID-19 [118]. In a computational study, drugs such as carfilzomib, valrubicin, eravacycline, lopinavir, and elbasvir inhibited the main protease in SARS-CoV-2. Further studies are required to confirm the efficacy of these drugs. Saquinavir and other protease inhibitors such as indinavir, amprenavir, and nelfinavir might also show the same effects against COVID-19 like protease inhibitors, due to resemblance between the structures. In a computer simulation, saquinavir and indinavir were found to suppress 3CLPro activity in SARS-CoV-2 [119]. In vitro inhibition of SARS-CoV-2 was shown to be inhibited by saquinavir, indinavir, amprenavir, and nelfinavir, with nelfinavir demonstrating the greatest suppression when compared with the others. In Singapore, saquinavir has been used to treat COVID-19 patients. Two other medications, raltegravir and paritaprevir, were shown to have the ability to block 3CLPro activity in SARS-CoV-2 in a computational investigation (Tables 1 and 2) [120].
Class | Drugs | Application | Emergency use for COVID-19 |
---|---|---|---|
Fusion inhibitor | Umifenovir (Arbidol) | Influenza | Singapore, China |
Protease Inhibitor | Lopinavir | HIV | USA, Japan, Singapore, Italy, China, IPC (Lopinavir-Ritonavir fix dose) |
Darunavir | HIV-1 | Italy (Darunavir-Ritonavir fix dose) | |
Atazanavir | HIV-1 | Singapore | |
Saquinavir | HIV-1 | Singapore | |
Nucleoside reverse transcriptase inhibitor | Emtricitabine | HIV-1 | Singapore (Emtricitabine-Tenofovir fix dose) |
Azvudine | HIV-1 | Singapore | |
Nucleotide reverse transcriptase inhibitor | Remdesivir | Ebola | WHO, IPC, USA, Singapore, Italy |
Favipiravir | (Avigan) Influenza | Singapore, Japan, Indonesia | |
Ribavirin | HCV | Singapore, IPC | |
Sofosbuvir | HCV | Singapore | |
Neuraminidase inhibitor (Virus release inhibitor) | Oseltamivir (Tamiflu) | Influenza A & B | IPC, Singapore, Indonesia |
Current use of existing antiviral drugs for COVID-19 [56].
International Pulmonologists’ Consensus includes the USA, India, Iran, China, Italy, Great Britain, EUA, Colombia, Egypt, Singapore, Romania, Ireland, Malaysia, Saudi Arabia, Sudan, Greece, and Bolivia.
Group | Drugs | Mechanism of action |
---|---|---|
Viral RNA polymerase inhibitors | Remdesivir (GS-5734) | RdRp inhibitor, prodrug, the analog of adenosine nucleotide |
Favipiravir | RdRp inhibitor, prodrug, the analog of guanosine nucleotide | |
Viral protein synthesis inhibitors | Ritonavir/Lopinavir | Inhibitor of protease |
Inhibitors of viral entry | Hydroxychloroquine Chloroquine | Increase in endosomal pH needed for the virus/cell fusion. Interfere with cellular receptor glycosylation of SARS CoV (ACE-2) |
Immunomodulators | Nitazoxanide | Interfere with host regulated pathways of virus replication, amplification of type 1 IFN pathways, and cytoplasmic RNA sensing |
Ivermectin | Inhibition of importin 1 heterodimer to inhibit the nuclear import of host and viral proteins |
Mechanism of action of antiviral drugs used for the treatment of COVID-19.
Another technique for combating SARS-CoV-2 infection is to inhibit RdRp and impede viral replication by targeting the reverse transcription process. Nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and nucleoside reverse transcriptase translocation inhibitors are a few examples of possible inhibitors (NRTTIs).
Other NtRTIs with comparable structural properties to remdesivir or ribavirin, such as adefovir, tenofovir alafenamide, tenofovir disoproxil, abacavir, ganciclovir, and didanosine, exhibit antiviral effectiveness against SARS-CoV-2. NRTIs (lamivudine, stavudine, zidovudine, emtricitabine, zalcitabine, and azvudine) and NNRTIs (efavirenz, nevirapine, delavirdine, and rilpivirine) may also have antiviral activity against SARS-CoV-2 [56].
Oseltamivir is a neuraminidase inhibitor used in preventing influenza Neuraminidase inhibitor drugs such as oseltamivir, zanamivir, and peramivir are antiviral drugs that inhibit the viral neuraminidase enzyme and are recommended for influenza and to block the release of viral particles out of host cells. Neuraminidase inhibitors are also used as empirical treatment in MERS-CoV infection [121, 122]. However, a combination of oseltamivir with ganciclovir and lopinavir/ritonavir is used to treat COVID-19 patients [40]. A computational study also supported synergistic effects of oseltamivir-lopinavir-ritonavir combination against SARS-CoV-2 [123]. Oseltamivir is used with ceftriaxone and terbutaline to treat COVID-19 [124]. A study showed that the CT scan of the lungs of a COVID-19 patient showed significant improvement after a three-day course of oseltamivir [19]. Oseltamivir has been used either with or without antibiotics and corticosteroids against COVID-19. In a clinical trial, oseltamivir is tested with chloroquine and favipiravir [93, 125].
Nowadays, the rising SARS-CoV-2 turned into a global threat. COVID-19 targets lung cells by connecting to ACE2 protein. This protein is largely produced in some tissues such as the bile duct, liver, gastrointestinal organs, esophagus, testis, and kidney as well as lung tissue. Thus, COVID-19 may damage these organs and tissues. With the global threatening caused by COVID-19, efficient therapy against COVID-19 is quickly necessary. Nevertheless, the development of new drugs for this disease is still a huge problem for people in the world, and we have none formally approved drugs against COVID-19 now. It is very crucial to cut off the extending of this virus owing to epidemic avoidance and checking techniques. We need to develop novel drugs and to find new therapy methods to prevent this outbreak and to treat COVID-19. The extent of the current pandemic, along with other factors, such as the lack of time to develop novel and effective agents against COVID-19, the high mortality rate, possible mutations in its genetic material and severe economic shocks to societies highlight the value of testing antiviral drugs present in our drug arsenal. Some drugs that have already started with repositioning may be effective against COVId-19 as well. It is essential to address the drug-drug interaction of the drugs in COVID-19 patients with comorbidities. We hope that the continuing studies may provide solutions for the prevention and therapy against the COVID-19.
Despite the fact that specific antiviral medications for COVID-19 have yet to be identified or authorized by the FDA, the usage of some currently existing antiviral agents that target various phases in COVID-19’s life cycle might be an alternate therapeutic strategy for combating the pandemic. Fusion inhibitors, protease inhibitors, and transcription inhibitors are just a few of the interesting antiviral medication classes to investigate. Apart from antiviral medicines, various interesting techniques to treating COVID-19 are being employed, such as convalescent plasma, which has been found to reduce viral load and patient morbidity. The effects of interferon (IFN)-α/β and IL-6R inhibitor1 have also been encouraging [126, 127, 128]. The introduction of several new technologies is likely to yield good benefits. The safety of patients should be prioritized while evaluating new SARS-CoV-2 vaccinations. Nanotechnology offers an effective new route for diagnostics and treatment techniques. The more distinctive nanoparticles operate as excellent antiviral medication delivery vehicles, increasing the procedure’s effectiveness. Finding appropriate diagnostic and therapeutic strategies for the fast and efficient care of severe COVID-19 patients is urgently needed [129, 130]. Different research on different CoV-induced diseases shows that using α-interferon, chloroquine phosphate, arabinol, remdesivir, lopinavir/ritonavir, and anti-inflammatory medications might result in encouraging clinical results for SARS-Cov-2 patients. Tocilizumab should be used as a therapy approach for severe COVID-19 pneumonia to achieve favorable results. Furthermore, further clinical studies with appropriate medications should be conducted on SARS-CoV-2 patients to demonstrate effectiveness and safety.
We are thankful to the Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, 21955, Saudi Arabia, and Glocal School of Pharmacy, Glocal University, Mirzapur Pole, 247121, Saharanpur, Uttar Pradesh, India for providing necessary facilities.
The authors declare no conflicts of interest.
3CLpro | 3-chymotrypsin-like protease |
AAK1 | AP2-associated protein kinase 1 |
ACE2 | angiotensin-converting enzyme 2 |
ACEi | angiotensin-converting-enzyme inhibitors |
ADR | acute respiratory distress syndrome |
AIDS | acquired immunodeficiency syndrome |
Cm | maximum concentration |
CMV | cytomegalovirus |
COVID-19 | coronavirus disease 2019 |
DCGI | drug controller general of India |
DR | drug repurposing |
E | envelope protein |
ER | endoplasmic reticulum |
ERGIC | endoplasmic reticulum-Golgi apparatus compartment |
EVD | Ebola virus disease |
HA | hemagglutinin envelope glycoprotein |
HAV | hepatitis A virus |
HCMV | human cytomegalovirus |
HCV | hepatitis-C virus |
HE | hemagglutinin esterase |
HSV | herpes simplex virus |
ICU | intensive care unit |
INF-β | interferon |
Kb | kilo base pairs |
M | membrane protein |
MERS | Middle-East Respiratory Syndrome |
Mpro | main protease |
N | nucleocapsid |
NNRTI | non-nucleoside reverse-transcriptase inhibitors |
NRTTI | nucleoside reverse transcriptase translocation inhibitors |
NtRTI | nucleotide reverse-transcriptase inhibitor |
PLPro | Papain-like protease |
qRT-PCR | quantitative real-time polymerase chain reaction |
R0 | reproductive number |
RdRp | RNA-dependent RNA polymerase |
RNA | ribonucleic acid |
RVFV | Rift Valley fever virus |
S(P) | Spike protein |
S | glycoprotein spike |
SARS | severe acute respiratory syndrome |
SARS-CoV-2 | Severe acute respiratory syndrome coronavirus 2 |
SPs | spike proteins |
TMPRSS2 | transmembrane serine protease 2 |
US FDA | United States Food and Drug Administration |
WHO | World Health Organization |
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Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. 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He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. 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He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. 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She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",country:{name:"Spain"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}}]}},subseries:{item:{id:"9",type:"subseries",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. 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