Combinatorial Antiviral Regimen as Strategy to Control SARS-CoV-2 Infections

The coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have impacted health of the people and economy globally. Despite multiple vaccines have been authorized for emergency use, the continuous emergence of SARS-CoV-2 variants of concern (VOCs) with enhanced infectivity and transmissibility, as well as resistance to antibody neutralization from vaccine-elicited sera and convalescent plasma, has become a major obstacle against ending the COVID-19 epidemic. Although several antivirals with SARS-CoV-2 inhibitory activity have been approved for the clinical use to treat COVID-19, only a few have shown significant clinical efficacy. Many antivirals are either less effective or may cause serious side effects or resistance and are no longer recommended for the treatment of COVID-19. Therefore, the development of potent and broad-spectrum antivirals to inhibit SARS-CoV-2 and its variants and treat COVID-19 is urgently needed. Antiviral therapeutics can be directed at the host or at the virus. Therefore, in-depth understanding of the virus interaction with the host as well as steps of virus replication is very important. Here we provide insights into the different targets, both virus and host, and discuss the critical components. SARS-CoV-2 genome encodes two open-reading the non-structural protein 5 (NSP5) main protease (Mpro), and the NSP3 papain-like protease (PLpro). Here we screened different compounds targeting main protease (Mpro) and PLpro using high throughput antiviral assays, computational docking, enzymatic and binding assays, and cells-based assays. Similarly, we screened a potent target host protease inhibitor against SARS-CoV-2 and its variants. Mono therapeutic regimen sometimes results in the development of drug resistance strains, especially when given to immune-compromised patients. Therefore, combinatorial antiviral regimens targeting different enzymes that are essential for viral replication are important, as they have less toxicity and blunt the evolution of mutant strains. We used a combinatorial antiviral approach to investigate the synergistic effect of compounds with the previously FDA approved drugs for COVID-19 treatment like Remdesivir, Molnupiravir, and Nirmaletrelvir. In conclusion, we identified compounds with potent antiviral activity against the SARS-CoV-2 and the latest circulating variants of SARS-CoV-2. These compounds when combined with FDA-approved antiviral drugs for for COVID-19, exhibit a synergistic/additive effect, that warrants validation of these findings in preclinical models to treat the persistent SARS-CoV-2 replication.