Fighting COVID-19: potential targets for drug design

ABSTRACT

Coronaviruses have emerged as important agents of human infection. SARS-CoV-2, the causative agent of COVID-19, has triggered a global pandemic with devastating consequences. The understanding of fundamental aspects of these viruses is of extreme importance. Fast vaccine development has been a crucial factor in preventing serious disease, but the fast-paced emergence of new variants raises many problems. Viral non-structural proteins are fundamental for viral replication. SARS-CoV-2 nsp16 is a 20-O-methyltransferase with a pivotal role in Interferon antagonism. Nsp16 methylates viral RNA to mimic the host mRNA and then the cell stops recognizing it as foreign. This activity is stimulated by the interaction with nsp10. This protein also acts as a co-factor for the exoribonucleolytic activity of nsp14. Nsp14 also has significant anti-interferon importance that stems from its 2 distinct activities the N-terminal 3'-to-5' exoribonuclease (ExoN) and a C-terminal N7-methyltransferase (N7-MTase). Unlike Spike proteins, these nsp10, nsp14, and nsp16 are highly conserved among viral variants. In this work, we are studying them and finding inhibitors in order to develop new therapies. Nsp10 is the prime target of our focus since it is the central player in the regulation of both nsp14 and nsp16.