An Update on Antiviral Therapy Against SARS-CoV-2: How Far Have We Come?

Abstract

COVID-19 pandemic has spread worldwide at an exponential rate affecting millions of people instantaneously. Currently, various drugs are under investigation to treat an enormously increasing number of COVID-19 patients. This dreadful situation clearly demands an efficient strategy to quickly identify drugs for the successful treatment of COVID-19. Hence, drug repurposing is an effective approach for the rapid discovery of frontline arsenals to fight against COVID-19. Successful application of this approach has resulted in the repurposing of some clinically approved drugs as potential anti-SARS-CoV-2 candidates. Several of these drugs are either antimalarials, antivirals, antibiotics or corticosteroids and they have been repurposed based on their potential to negate virus or reduce lung inflammation. Large numbers of clinical trials have been registered to evaluate the effectiveness and clinical safety of these drugs. Till date, a few clinical studies are complete and the results are primary. WHO also conducted an international, multi-country, open-label, randomized trials-a solidarity trial for four antiviral drugs. However, solidarity trials have few limitations like no placebos were used, additionally any drug may show effectiveness for a particular population in a region which may get neglected in solidarity trial analysis. The ongoing randomized clinical trials can provide reliable long-term follow-up results that will establish both clinical safety and clinical efficacy of these drugs with respect to different regions, populations and may aid up to worldwide COVID-19 treatment research. This review presents a comprehensive update on majorly repurposed drugs namely chloroquine, hydroxychloroquine, remdesivir, lopinavir-ritonavir, favipiravir, ribavirin, azithromycin, umifenovir, oseltamivir as well as convalescent plasma therapy used against SARS-CoV-2. The review also summarizes the data recorded on the mechanism of anti-SARS-CoV-2 activity of these repurposed drugs along with the preclinical and clinical findings, therapeutic regimens, pharmacokinetics, and drug-drug interactions.

Keywords: COVID-19; SARS-CoV-2; antivirals; drug repurposing; mechanism of action; pharmacokinetics.

FIGURE 1

Proposed mechanisms of repurposed drugs and therapies used against SARS-CoV-2 infection. SARS-CoV-2 interacts with cell surface receptors like ACE-2 and neuropilin to gain entry inside the cell. Umifenovir may interact with SARS-CoV-2 surface glycoproteins and lipids and obstruct the interaction with the entry receptor ACE-2. Anti-SARS-CoV-2 antibodies present in convalescent plasma may inhibit SARS-CoV-2 entry and subsequent infection transmission. Chloroquine, hydroxychloroquine and azithromycin may elevate endosomal pH and hinder viral entry and RNA release process. Chloroquine, hydroxychloroquine and azithromycin also shows immunomodulatory effects. Nucleoside inhibitors like remdesivir, favipiravir and ribavirin may inhibit RNA replication and suppress RNA-dependent RNA polymerase activity. Lopinavir may fraternize with viral protease altering the proteolysis. Oseltamivir may interplay with components involved in the exocytosis process, blocking the viral exit from the cell. Monoclonal antibodies against cytokine receptors and Corticosteroid shows anti-inflammatory actions against exaggerated immune response. (ACE-2-Angiotensin-converting enzyme 2, TMPRSS2 Transmembrane Serine protease 2, RdRp- RNA dependent RNA polymerase, ER- Endoplasmic reticulum, ERGIC- Endoplasmic reticulum-golgi intermediate complex. The displayed ACE-2-Spike interaction residues and RdRp structures are based on Protein databank structure ID: 6M0J and 6M71 respectively).