**5. Drugs under clinical trials for COVID-19**

As the epidemic spreads more and more, scientists worldwide are in a quest to explore drugs that may be potentially effective in combating COVID-19. During a pandemic that causes morbidity and mortality to grow exponentially, well-structured, randomized, controlled trials are necessary to evaluate new or repurposed drugs' safety and efficacy to protect the community from ineffective, unnecessary, or unsafe drugs [55]. World Health Organization and partners have launched an international clinical trial – Solidarity trial, to assist in the accelerated search for a therapeutic regimen for COVID-19. Solidarity trail is one of the most extensive international randomized trials for COVID-19 to evaluate drugs on three essential outcomes that were needed for assisted ventilation, mortality, and duration of hospital stay. Solidarity Trial also aims to assess the chances of drugs improving survival or reducing the need for ventilation or hospital stay duration [56]. Currently, repurposed antiviral therapies are under significant scrutiny in clinical trials as disease-specific and designated antiviral therapy may have a maximum impact on disease progression and optimized treatment of COVID-19 [57].

#### **5.1 RNA mutagens**

RNA and DNA viruses encode RNA-dependent RNA polymerase (RdRp) core, which is requisite for RdRP catalytic function and viral replication. Hence, it is one of the prime targets for intervention infection. RdRp facilitates the elongation of the RNA strand and genome replication [7, 58]. RNA mutagens are nucleotide analogs that halt RNA elongation by RdRp by inserting themselves into the RNA chain. RdRp has no host cell homolog making this antiviral drug development superior as it reduces the risk of affecting human cells or protein. Thus, mutagenic nucleoside analog inhibitors like remdesivir, favipiravir, and ribavirin targeting RdRp are explored for their function to block viral RNA synthesis against human coronaviruses [7].

Remdesivir is a known antiviral against SARS-CoV and the MERS-CoV and has been a drug choice for SARS-CoV-2 due to its proven activity to inhibit SARS-CoV-2 in vitro [59]. A randomized, placebo-controlled, double-blind trial of intravenous remdesivir in hospitalized adults suffering from lower respiratory tract infection due to COVID-19 shows an average recovery day of 14 days and clinical improvement at day 15, emphasizing that remdesivir abbreviate time to recovery among COVID-19 patients. The trial also suggested that a remdesivir treatment regimen may prevent disease progression to more severity and a lower incidence of respiratory support requirement [60]. Another randomized, openlabel trial among patients with severe COVID-19 who required oxygen support showed recovery among patients with both 5- and 10-day courses of remdesivir [61]. In another randomized phase 3 clinical trial, compared to standard of care treatment, the period of 5 days of remdesivir had significant improvement in patient's clinical status [62]. Prompted by such conclusive evidence, the US Food and Drug Administration has granted remdesivir a status of Emergency Use Authorization for SARS-CoV-2 infected patients of about 12 years of age and with pneumonia [57].

Favipiravir is a broad-spectrum oral RNA-dependent RNA polymerase (RdRp) currently under study in numerous clinical and preclinical trials for its Role in inhibiting the viral replication phase of SARS-CoV-2. Glenmark Pharmaceuticals evaluates Favipiravir in Phase 3 clinical trial for COVID-19 among mild to moderately infected patients of COVID-19 and has observed a marked 40% faster recovery of patients by day 4 [63].

In another prospective, randomized, controlled, open-label multicentered trial involving adult patients with COVID-19 in china, Favipiravir, compared to Arbidol, significantly improved the viral clearance, relief for pyrexia and cough with mild and manageable adverse effects [64]. Such promising results have cast the attention of healthcare providers to use RNA mutagens in treatments for SARS-CoV-2 infection [65].
