COVID-19 Drug Development: Role of Drug Repurposing

Abstract

The COVID-19 pandemic came at a time when the scientific world was least prepared for it. It emerged at a time when there were variable research availability and limited mechanistic insights about the virus. Amid these challenges, research works were carried out in a bid to discover ways of curbing the spread of the virus and improving the health outcome of the population. Drug repurposing was one concept that was explored by scientists. Through this concept, already existing drugs were repurposed for the treatment of COVID-19, with incredible results seen. This chapter provides insights on some repurposed drugs, steps taken in drug repurposing, challenges peculiar to the methods, and a framework for continuity.

1. Introduction

Coronaviruses, a large group of positive-sense RNA, single-stranded, and enveloped viruses have been one of the viral sources of respiratory diseases [1]. In December 2019, they caught the attention of the world when a strain of the virus-n-CoV-19, which was later renamed SARS-CoV-2 virus-caused epidemic cases of respiratory tract infection in Wuhan, China. The initial cases were presumed to be complications of pneumonia and were treated as such, until when further studies were conducted as regards the rate of spread, morbidity, and mortality of the disease [2]. Findings from studies conducted provided evidence that made the World Health Organization (WHO) declare the disease as a global health emergency and subsequently a pandemic.

For the first 12 months since the inception of the pandemic, COVID-19 spread worldwide, gravely affecting countries such as Turkey, Iran, Poland, Mexico, Germany, Colombia, Argentina, Spain, Italy, United Kingdom, France, Russian Federation, Brazil, India, and the USA, with each country recording over 1 million confirmed cases (https://covid19.who.int/accessed on August 25, 2022). The lack of proper treatment and vaccine made the mortality rate quite high [3].

Some of the measures used in curbing the spread of the virus and improving the quality of life of those infected included national and international lockdown, travel restrictions, mandatory use of face covering, washing of hands, and social distancing [4]. Also, some drugs were repurposed for the management of the disease, and vaccines were developed. Figure 1 shows the timeline of the COVID-19 pandemic and details of some repurposed drugs used [5].

Figure 1.

Showing the timeline of the COVID-19 pandemic and details of repurposed drugs used [5, 6, 7, 8, 9].

2. Historical overview of drug repurposing

Drug repurposing, also known as indication shift, indication expansion, drug proofing, or drug repositioning, involves establishing a new medical use for an already known drug. These drugs can be experimental, shelved, discontinued, or already approved. Although drug repurposing is not a new strategy, it has gained wide recognition in recent times in the pharmaceutical sector [10].

The procedure to authorize a new medicine is costly and can take 10–15 years. This drawn-out discovery process makes drug repurposing (repositioning) a viable alternative strategy for reducing the amount of time needed to produce medicine. This original concept of drug repositioning has since been expanded to encompass active ingredients that failed the clinical stage of their development due to their toxicity or insufficient efficacy, as well as medications pulled off the market due to safety concerns. However, compounds that have not yet been the focus of clinical research should not be included. This specifically disallows chemicals maintained in chemical libraries by academic and industrial research groups from being screened to find new biological qualities, apart from the properties for which they were initially developed and synthesized. Thus, any changes to the drug’s structural makeup are not included in the idea of drug repositioning. Instead, repositioning uses either the biological properties for which the drug has already received approval (possibly in accordance with a different formulation, at a new dose, or via a new route of administration) or the side properties of a drug that are accountable for its negative effects in a new indication. The fact that various diseases share occasionally similar biological targets, as revealed by the elucidation of the human genome, and the idea of pleiotropic medications, serve as the two fundamental scientific foundations for therapeutic repositioning [11, 12]. Repurposing a medicine involves using it for a different indication after having it licensed by a regulatory body like the FDA, the European Medicines Agency (EMA), or the Medicines and Healthcare Products Regulatory Agency (MHRA), among others. Many pharmaceutical companies are presently using drug repurposing to regenerate some of their FDA-approved and previously unsuccessful pipeline molecules as novel medicines for a variety of illness conditions due to the enormous promise of a reduced development cycle [13, 14].

One of the keys to drug repurposing is the description of the factors related to the complicated interplay between diseases, medications, and targets using in silico methodologies (data mining, machine learning, ligand-based, and structure-based approaches). Today, diseases can be described in terms of their molecular profile (including the genes, biomarkers, signaling pathways, and environmental factors), and the degree of similarity between diseases that share a number of these molecular features can be assessed using computational methods, particularly data mining. Protein targets that are shared by a number of diseases imply that a given medication may be effective in treating both disorders [12, 15, 16, 17]. In terms of their core therapeutic effects and their (generally undesirable) side effects, the majority of medications are now phenotypically well described. The drug’s pleiotropic interactions with a number of (primary and secondary) biological targets cause this variety of side effects. Therefore, if one of a medicine’s secondary targets plays a part in an illness different than the one for which it was initially intended, the treatment may be effective against the new disease. Be aware that these pleiotropic interactions allow for the development of medications with many, intended effects that work in concert to increase clinical efficacy, such as the pan-kinase inhibitors used in cancer. Regardless of their therapeutic reason, medications can be analyzed for phenotypic similarities much like diseases are. A medicine may be successful for both indications if it has a high similarity score to another treatment designated for a separate condition [10, 16].

2.1 Significance of drug repurposing

Drug repurposing reduces the development cost for drugs because they have already gone through clinical trials, toxicity studies, and other tests [18]. Tables 1 and 2 below show a list of some repurposed drugs in the past.A recent analysis based on a survey of 30 pharmaceutical and biotechnology companies found that the average cost to re-launch a repurposed drug is $8.4 million, compared to an average cost of $41.3 million for a new formulation of an existing drug in its original indication [20]. They have a higher success rate than the original drugs, owing to the availability of comprehensive information on their pharmacology, formulation, potential toxicity, safety, and adverse drug reaction issues, thereby reducing their attrition rate [21]. Since repurposing is based on prior research and development efforts, new drug candidates could be promptly prepared for clinical trials, hastening the FDA’s review of them and, if approved, their introduction into healthcare, shortening the time it takes for the full processing cycle. Re-profiled medications also save the upfront costs and delays associated with bringing a drug to market, because it takes a great deal of time, money, and effort to produce a new medicine. In general, it frequently takes more than 15 years to convert a potential therapeutic candidate into an approved medication [22]. Therefore, it is essential to develop drug repurposing procedures in order to reduce the time and cost of drugs while also raising their success rates. In addition, repurposed compounds have a market penetration rate of 25% from Phase II and 65% from Phase III clinical trials, compared to 10% and 50%, respectively, for novel molecular entities [23].

S/N	Drug name	Original indication	New indication	Mechanism of action	Status of study	Ref.
1	Itraconazole	Antifungal	Prostate cancer	Reducing prostate-specific antigen (PSA) levels	Phase 2	[19]
2	Metformin	Type 2 Diabetes	Advanced prostate cancer	Inhibition of the mammalian target of rapamycin complex 1 (mTORC1) pathway	Phase 2	[19]
3	Aspirin	Fever and pain	Melanoma	Stop the growth of tumor cells by blocking some of the enzymes needed for cell growth	Phase 2	[11]
4	Sildenafil	Angina pectoris	Erectile dysfunction	Phosphodiesterase type 5 (PDE5) inhibition	Approved	[11]
5	Thalidomide	Morning sickness	Multiple myeloma	Antiangiogenic	Approved	[11]
6	Sodium Nitrite	Antidote to cyanide poisoning	Chronic leg ulcers associated with sickle cell and other blood disorders	Vasodilation	Recruiting participants for clinical trial	[11]
7	Celebrex	Osteoarthritis	Reduce the risk of additional polyp formation in colon cancer	Inhibiting COX-2 receptors	Approved	[11]
8	Dapsone	Leprosy	Malaria	Inhibit bacterial dihydropteroate synthase	Phase 3 completed	[11]
9	Amphotericin	Antifungal	Leishmaniasis	Disruption of parasite membrane	Phase 3 completed	[11]
10	Eflornithine	Cancer	African trypanosomiasis	Inhibition of ornithine decarboxylase (ODC)	Phase 3 completed	[11]

Table 1.

List of some drugs that have been repurposed.

S/No	Repurposed drug for COVID-19	Previous indication
1	Azithromycin	An antibiotic used for the treatment of respiratory and urinary tract infections
2	Mavrilimumab	Rheumatoid arthritis
3	Baricitinib	Rheumatoid arthritis
4	Hydroxychloroquine sulfate and chloroquine phosphate	Amoebic dysentery and malaria
5	Lopinavir-ritonavir	HIV/AIDS treatment and prevention
6	Favipiravir	Influenza
7	Dexamethasone	Asthma, allergies, skin diseases

Table 2.

List of some repurposed drugs for the treatment of COVID-19.

For a new investigational molecule, safety and efficacy data are not yet available, resulting in higher attrition during the drug discovery process leading to the most failures regarding safety or efficacy. By contrast, all safety, preclinical, and efficacy data are readily available for a repurposed molecule, thus enabling the investigator to make an informed decision at each stage of drug development [23, 24]. Availability of prior knowledge regarding safety, efficacy, and the appropriate administration route significantly reduces the development costs and cuts down the development time resulting in less effort required for successfully bringing a repositioned drug to market [25]. For example, sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, represents one of the successful repurposing efforts. Sildenafil was originally developed for hypertension treatment but was later identified to have significant benefits in erectile dysfunction and was approved by the FDA for the same. It was later repurposed for the treatment of a rare disorder: pulmonary hypertension [26]. Also, daptomycin (an antibacterial agent) was repurposed for the treatment of Zika virus infection, chlorcyclizine (an antihistamine) was repurposed for the management of hepatitis C virus infection, and manidipine (an antihypertensive agent) was repurposed for Japanese encephalitis virus treatment [27].

3. Repurposed drugs for COVID-19 pandemic

Due to the urgent need for COVID-19 treatment options, all repurposed drugs were given emergency approval. Approval for hydroxychloroquine and chloroquine were later revoked due to the high number of cardiac toxicity recorded (Figure 2) [10].

Figure 2.

Main organ injury of SARS-CoV-2 infection [24].

4. A simplified scheme of the life cycle of SARS-CoV-2

Based on the likely mechanism by which registered pharmaceuticals combat the Coronavirus, the disease, or its symptoms, drug repurposing possibilities for COVID-19 can be categorized.

1. Drugs that disrupt the Coronavirus replication cycle.

2. Drugs that indirectly ameliorate the effects/symptoms of COVID-19 disease through direct influence on cellular immunity and metabolism.

4.1 Drugs that disrupt the Coronavirus replication cycle

The mechanism of many antiviral medications is hinged on the interruption of one or more replication phases of the virus.

4.1.1 Attachment and entry of the virus into the host cell

The first phase of the virus replication cycle is the attachment and entry of the virus into the host cell. There are two ways through which SARS-CoV-2 can gain entry into host cells. The first is through the binding interaction of SARS-COV-2 spike protein (S) with the ACE2 receptor and transmembrane protease serine 2 of the target cell (TMPRSS2), while the second is through endocytosis [28]. ACE2 is the coupling site for SARS-CoV-2 spike protein, while TMPRSS2 facilitates host cell entrance; therefore, some drugs that interfere with ACE2 or TMPRSS2 have the potential for being repurposed in the management of COVID-19 because they will prevent the entry of SARS-CoV-2 into host cells. In theory, drugs such as dexamethasone, estradiol, isotretinoin, retinoic acid, and spironolactone can influence the expression of ACE2, while drugs such as bicalutamide, bromhexine, camostat mesylate, and nafamostat act similarly with TMPRSS2 [28]. In an experiment involving SARS-CoV-2 spike pseudotyped virus, dexamethasone was found to bind to ACE2, preventing binding of the spike protein of the virus to ACE2 and preventing entry of the virus into the target cell [29]. This is the likely mechanism by which dexamethasone would find activity against SARS-CoV-2 as a repurposed drug. Similarly, bromhexine is a TMPRSS2 protease blocker that prevents viropexis of SARS-CoV-2 into target cells through its blocking effect on TMPRSS2 [28].

Viral attachment and entry into the host cell involve the attachment of spike protein of the SARS-CoV-2 to ACE2 and further involvement of TMPRSS2. If potential drugs for repurposing in COVID-19 treatment leverage their possible effects on ACE2 and TMPRSS2, then drugs that could influence the viral strike protein are also theoretically useful enough to be repurposed in COVID-19 treatment. One such drug is bamlanivimab.

Bamlanivimab is a recombinant human IgG1κ monoclonal antibody with activity against the spike (S) surface protein of SARS-CoV-2 itself, not the ACE2 or TMPRSS2 of the host cell [28]. Umifenovir and nelfinavir are antiviral medications. Umifenovir was previously used in the prophylaxis and management of influenza, while nelfinavir is an antiretroviral medication used in HIV. Umifenovir inhibits spike protein trimerization, while nelfinavir inhibits membrane fusion. This implies that both drugs have the potential for repurposing in COVID-19 management [28].

Endocytosis is a process through which cells take in foreign material by enveloping it with their membrane [29]. Research has shown that SARS-CoV-2 is capable of entering host cells by means of endocytosis. Drugs that prevent the entry of SARS-CoV-2 by endocytosis into the host cell can be repurposed in COVID-19. Such drugs include chloroquine, hydroxychloroquine, artemisinin, amodiaquine, chlorpromazine, niclosamide, imatinib, artesunate, baricitinib, verapamil, and amiodarone [28]. Many of these drugs work by inhibiting membrane fusion between SARS-CoV-2 spike protein and the host cell membrane.

4.1.2 Chloroquine and hydroxychloroquine

Chloroquine belongs to the chemical class of antimalarial medications called 4-aminoquinolines [30, 31]. Hydroxychloroquine (HCQ) is a derivative of chloroquine obtained by β-hydroxylation of the N-ethyl substituent of chloroquine to give hydroxychloroquine, which has a hydroxyl group at the end of the side chain. Chloroquine was known to be an effective drug in the treatment of malaria due to its high activity against the asexual erythrocytic forms of the plasmodium. This high profile of effectiveness was however affected negatively due to the growing cases of plasmodial resistance to available antimalarial agents. Although chloroquine was initially developed to treat malaria, the focus has largely shifted to its antirheumatic and antiviral activity. Over the past 20 years, a great deal of research has gone into the investigation of the antiviral effects of chloroquine [32].

As an antimalarial agent, chloroquine/hydroxychloroquine enters the feeding vacuoles of the malaria parasite where it prevents the conversion of heme (a toxic product of the breakdown of hemoglobin) to hemozoin (which is not harmful to the parasite). Accumulation of heme leads to the death of the malaria parasite.

As a repurposed drug for COVID-19, in order to prevent the fusion of SARS-CoV-2 with the host cell membranes, chloroquine/hydroxychloroquine is thought to work by blocking endocytic proteins and elevating the pH of the endosomes [33]. The endocytic pathway interference, sialic acid receptor blockage, limitation of pH-mediated spike (S) protein cleavage at the angiotensin-converting enzyme 2 (ACE2) binding site, and cytokine storm prevention are all part of the mechanism of action of chloroquine/hydroxychloroquine [34]. The major drawbacks of the use of chloroquine or hydroxychloroquine in COVID-19 treatment are adverse effects such as retinopathy, prolonged QT interval on the ECG, and cardiotoxicity [35]. Hydroxychloroquine is preferred to chloroquine due to its increased hydrophilic nature and decreased toxicity. Hydroxychloroquine is also better tolerated than chloroquine [36].

In recent years, rheumatoid arthritis, lupus erythematosus, and amoebic hepatitis have all been managed with chloroquine and its hydroxyl derivative, hydroxychloroquine as anti-inflammatory agents. Chloroquine exhibits potent antiviral action against a variety of DNA and RNA viruses, including HIV-1, Influenza A, Influenza B, Coronavirus (SARS-CoV2), and many more. Recent reports and published research revealed that chloroquine and hydroxychloroquine were linked to slowed COVID-19 progression and shorter symptom duration. In June 2020, however, FDA revokes the emergency use authorization of the use of both chloroquine and hydroxychloroquine in the management of COVID-19, thus discouraging its use [32, 33].

4.1.3 Viral replication

After attachment and entry of the virus into the host cell, the SARS-CoV-2 life cycle then proceeds to the release of the viral RNA genome into the cytoplasm and translation of the replicase genes, which develop the replicase transcriptase complex (RTC) [28]. RNA replication is carried out by RNA-dependent RNA polymerase RdRp, which is incorporated within the RTC [28, 37]. Favipiravir, tenofovir, sofosbuvir, clevudine, and a number of other drugs have been suggested for COVID-19 repurposing due to their inhibitory effect on RdRp [28, 38]. Remdesivir (in its active form) is a nucleoside analog that inhibits the SARS-CoV-2 RdRp thereby preventing further replication of SARS-CoV-2 [39]. Other RNA replication inhibitors include ivermectin, mefloquine, doxycycline, emtricitabine, and tacrolimus.

After viral RNA replication, comes the translation of viral structural proteins. Atazanavir, saquinavir, lopinavir, and ritonavir were considered repurposing candidates for COVID-19 based on their activity as protease inhibitors (just as they are HIV protease inhibitors). This phase involves proteolytic processing of viral proteins, thus the use of protease inhibitors to interfere with and prevent the translation of proteins [28].

4.1.4 Viral assembly and release

This phase comprises of formation of mature virions and exocytosis. Progeny viruses are assembled in the endoplasmic reticulum-Golgi intermediate complex following the synthesis and processing of the viral structural proteins and are then transported in vesicles to be released by exocytosis. Candidates for repurposing include antiviral medications that target this phase of SARS-CoV-2 replication. Oseltamivir and daclatasvir are such medications [28]. Daclatasvir inhibits viral assembly while oseltamivir inhibits virus release. Oseltamivir interacts with exocytosis-related elements, preventing the viral escape from the cell [40]. Oseltamivir is effective for a number of avian influenza virus strains and functions as a neuraminidase inhibitor against the influenza virus [41].

4.2 Drugs that indirectly ameliorate the effects/symptoms of COVID-19 disease through direct influence on cellular immunity and metabolism

This group of drugs acts by completely different mechanisms as they do not share structural similarities. Some of them include dapaglifozin, leflunomide, plitidepsin, nitazoxanide. Nitazoxanide demonstrates broad-spectrum antiviral action against several viral diseases. Nitazoxanide showed good in-vitro activity against SARS-CoV-2 in cell culture experiments, showing potential for repurposing in COVID-19 [41]. Nitazoxanide has shown great promise in vitro, with a low IC50 against SARS-CoV-2. Nitazoxanide phosphorylates protein kinases activated by dsRNA to increase phosphorylated kinases activated by dsRNA to increase phosphorylated factor 2α. Factor 2α is an intracellular protein possessing antiviral activities [28]. Despite the potential effectiveness of these drugs, further in vivo and clinical testing are required.

5. Conclusion

The COVID-19 pandemic, though unprecedented, gave room for new insights and perspectives in different sectors of the world, including drug development. Drug repurpose came in handy in the fight against the pandemic by providing tentative treatment options for the prevention and treatment of the virus.

Conflict of interest

The authors declare no conflict of interest.