Introductory Chapter: Current Perspective of COVID-19 Drugs

1. Introduction

1.1 Early efforts of drug repurposing

When WHO declared that the COVID-19 pandemic was in place on March 2020, there were no standard drugs available for this new disease. One of the fastest and the most effective solution to face this problem is relying on the drug repurposing effort. Remdesivir is one of the earliest repurposed drug, as it has been originally develop for hepatitis C, and already examined for application in Ebola and Marburg virus infection [1, 2]. In the laboratory setting, remdesivir has been proven to inhibit the RdRp protein of SARS-CoV-2 that is responsible for viral replication, shortens hospitalization period, and is supported with vivid computational model [2, 3, 4, 5]. Hence, remdesivir could only be provided in hospital as it should be delivered intravenously to the patients, thus deterring out-patient application [6]. In parallel, some other repurposing efforts are on the way as well.

These anti-worm and anti-parasitic drugs, Ivermectin, Chloroquine, and Hydroxychloroquine, are also repurposed. Although they provide promising in vitro and in vivo leads, there are inconclusive clinical trial results. Moreover, some meta-analysis results provide some leads that are yet to be validated in the clinical trials [7, 8, 9, 10, 11, 12]. Hence, there are some repurposed drugs that are efficacious to reduce the severe effects of COVID-19, although they are not anti-viral ones. Dexamethasone, a long-standing standard drug of anti-inflammation and anti-coagulation, could inhibit the ‘cytokine storm’ of late stage COVID-19 [13]. It also acts as immune modulator as well [14, 15]. Then, Heparin that works as anti-blot clot drug, also deployed to the COVID-19 patients [16, 17, 18, 19]. However, during the early phase of COVID-19 pandemics, there are no standard drugs that could provide solid clinical evidence and could be deployed in out-patients.

2. Ascendancy of standard drugs for COVID-19

The development of Paxlovid and Molnupiravir, both of them are synthetic drugs, have enabled new standard due to the emergency FDA’s authorization [20, 21]. As nucleoside analogue, molnupiravir has successfully inhibited RdRp protein of SARS-CoV-2 while providing significant clinical trials result for patients with mild-to-moderate symptoms of COVID-19 [22]. Thus, Paxlovid, which is a combination of two distinctive drugs of nirmatrelvir dan ritonavir, could inhibit SARS-CoV-2’s main protease enzyme with retaining its acceptable concentration in the blood, and reduces hospital admission alongside with mortality rate significantly [23, 24]. Hence, both drugs were optimized with rational drug design methods and approved by the FDA with emergency authorization [22, 23, 24, 25, 26]. Although remdesivir has provided significant efficacy in the clinical setting, its in-patient setting prevented the wide-spread use. However, the development of oral remdesivir has been devised and the current status is deemed successful in the in vivo trials [27, 28]. Although careful and thorough examination by medical specialist is necessary before deploying those anti-viral drugs, they are considered the available standard drugs for COVID-19 so far.

3. FAERS database annotation of COVID-19 drug trials

FDA Adverse Event Reporting System (FAERS) Public Dashboard is the Bioinformatics approach in curating side effects of drug trials from clinical data [29, 30]. It has special public dashboard for COVID-19 emergency use authorization (EUA) products, as seen in the Figure 1.

Figure 1.

COVID-19 emergency use authorization (EUA) FAERS public dashboard (source: https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard).

The FAERS database has annotated COVID-19 drug trials side effects, such as the trials with hydroxychloroquine/chloroquine, bamlanivimab, Ribavirin-Interferon and ivermectin [31, 32, 33, 34, 35, 36, 37]. Moreover, cancer patients who were old (65 year-old and above), males, and taking immunosuppressive treatment, as well as those with hematological malignancies, were at a higher risk of death due to COVID-19 infection, according to FAERS data [34]. Hence, pertaining the existing COVID-19 standard drugs, the finding in FAERS database did not affect current FDA’s endorsement as it is considered still a relatively novel development. More trials will be necessary. Thus, extensive computational and wet lab studies of the leads’ pharmacological and toxicological properties should be carefully examined [38].

4. Promise of natural product leads

Since the early phase of the pandemics, many researchers have tried to examine bioactive compounds such as propolis and others, from natural products source as leads for SARS-CoV-2 drug candidates [39, 40, 41, 42, 43, 44, 45, 46, 47]. Although these efforts are still on going up to now, the leads are still in experimental stage in general. Several leads were developed with computational approaches from natural products, albeit still no conclusive experimental evidence that leads into clinical trials [48, 49, 50, 51]. There is also effort for repurposing natural product leads, from H5N1 inhibitor lead compounds, that are yet to provide wet lab results [52]. One example of the lead compound with in silico potential for inhibiting SARS-CoV-2 is Juglanin, as visualized in Figure 2.

Figure 2.

Juglanin, provided as the lead for SARS-CoV-2 drug candidate based on in silico approach [53] (source: https://pubchem.ncbi.nlm.nih.gov/compound/5318717#section=2D-Structure).

Computation of natural products chemistry is a way to leverage the indigenous knowledge with modern science such as bioinformatics and biomedicine [48, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63]. It has achieve certain success in medical application, such as the chemotherapy agent of Taxol [64, 65]. However, there is no standard natural product-based drug yet for COVID-19 up to now. In general, existing COVID-19 standard drugs are repurposed drugs that mainly comprises of synthetic and semi-synthetic compounds [66, 67]. How natural products bioactive compounds will perform in this domain, it remains to be seen.

5. Coronavirus and anticipation of future pandemics

The SARS, MERS, and COVID-19 pandemics have taught us valuable lessons that coronavirus outbreak could not be underestimated. This particular virus has showcased themselves as constant menace to the public health. Therefore, it would need establishment of a dedicated research network world-wide to cater this challenge. The current pandemics has been predicted in quite a while. Based on WHO guidelines in 2015, it is stated explicitly that coronavirus has a prospect of becoming pandemic [68, 69]. There are hundreds or even thousands coronavirus species that potentially some of them could be spilled to human population from animals [68, 69]. Although conclusive evidence is still gathered on the moment, the existing leads are pointing to the spill over of coronavirus from bat as precursor of this on-going pandemic [70, 71, 72, 73]. As a RNA virus, it has high mutation rate for the genetic material, and as new SARS-CoV-2 variants emerged, it elicits potential to tamper the efficacy of the existing therapy [74, 75, 76, 77]. In these uncertain conditions, Biologics and/or biosimilars such as monoclonal antibody, polypeptide, and protein-based therapy are proposed as potential therapies for COVID-19 infections. Their high bioavailability in the cell is one of the strength in the pharmacokinetics properties [78]. Monoclonal antibodies therapy has been proven to provide good efficacy against COVID-19 in clinical setting [79, 80]. Moreover, some peptide-based leads are currently under development as COVID-19 drug candidates [81]. For siRNA, some in silico and wet lab research are underway, albeit the clinical application is yet to be determined [82, 83, 84]. In this end, more variative approaches are available as means to anticipate future coronavirus pandemics.

Acknowledgments

The authors would like to express their gratitude to the Indonesia International Institute for Life Sciences (i3L) Department of Research and Community Service (LPPM) for their support of this study. The authors wish to express their gratitude to the Direktorat Sumber Daya, Kementerian Pendidikan, Kebudayaan, dan Ristek, as well as LLDIKTI3, for giving Hibah Penelitian Dasar Berbasis Kompetensi 2022 No. 0054/E5/AK.04/2022.