COVID19 is a viral respiratory illness; a pandemic of which began in early December of 2019 [1, 2]. The now widely recognized illness is caused by the SARS-CoV2 virus. Vaccines are now available in the United States. Other countries have also developed vaccines. However, these may not be the best option for all individuals due to the potential autoimmune responses and other complications from vaccines [5]. Additionally, the available COVID19 vaccines may have limited effectiveness against new strains of the SARS-COV2 virus, such as Omicron [6]. Consequently, a threat from COVID19 and a need for effective therapeutics exists. Additionally, as suggested by the findings in this manuscript, COVID19 therapeutics may be able to be repurposed for the treatment of other viral infections.
SARS-CoV2, the virus that causes COVID-19, is a new member of the Orthocoronavirinae subfamily; genus Sarbecovirus. It is a novel coronavirus, and though homologous, it is not MERS-CoV or SARS-CoV [4]. This novel coronavirus has a similar replication mechanism as other coronaviruses, West Nile virus, Marburg virus, Ebola virus, dengue virus, and hepatitis C virus (HepC) which utilizes a positive-sense, single strand of RNA to encode its genome. The genome of SARS-CoV2 is replicated by non-structural protein 12 (nsp12), an RNA-dependent RNA polymerase (RdRp). This RNA dependency is like reverse transcriptase in HIV and HCV replicase (NS5B) in HepC.[7, 8]. The RdRp mechanism is also seen in other positive strand RNA viruses, such as rhinoviruses, that cause common colds, and, not surprisingly, the homologous MERS-CoV and SARS-COV. [7, 8]. An existing drug, remdesivir, targets the SARS-CoV-2 virus’s nsp12 [9, 10].
Inhibition of viral polymerases has proven effective in treating of viral infections, such as in the cases of HIV and HepC, and the effectiveness of this strategy has led to compassionate use of the drug, remdesivir, in the case of SARS-CoV2 [11–13]. While using existing drugs speeds the treatment to the field more quickly, the threat of second, third, and even more subsequent waves of COVID19, or other pandemic coronaviruses, necessitate treatments specifically targeted to coronaviruses and that have increased potency. This study sought novel, non-nucleoside inhibitors of SARS-CoV2’s nsp12. This strategy will allow for incorporating molecules from a greater chemical space to find more potent coronavirus nsp12-specific lead molecules. Additionally, we discovered that by targeting the viral polymerase's catalytic metal ion binding areas, we found compounds were also partially effective against HIV1 reverse transcriptase displaying up to 24.4% inhibition of HIV-RT at 10 µM compound. These compounds could be helpful against COVID19 and may be developable into a wider spectrum of antivirals.