Studies on SARS-CoV-2 Main Protease for developing antiviral therapy

Abstract

The worldwide outbreak of Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) created a state of chaos and panic all around the world. The disease has killed more than 6 million people worldwide since it was first reported in Wuhan, China in December 2019. Since the pandemic broke, several attempts have been made to find promising antiviral candidates. Scientific community around the world has been trying to decipher the complex biology of the virus by studying the numerous proteins that SARS-CoV-2 makes inside the host cells. Proteolytic cleavage plays a pivotal role in life cycle of the virus and the viral nsp-5 (non-structural protein-5) and nsp-6 are the two key proteases used by SARS-CoV-2 to produce functional peptides which help in the replication machinery of the virus. Nsp-5, also known as the Main Protease (Mpro) or 3 Chymotrypsin-like Protease (3CLpro), cleaves the polyprotein1ab, translated from ORF1ab of the viral genome, into different functional non-structural proteins. These proteins help in the formation of new infectious virions inside the host cells. Consequently, Mpro portrays as an attractive target for development of novel anti- viral agents due to its active importance in viral life cycle. Mpro is known to be a functional enzyme only in its dimeric form. Hence, targeting the dimeric interface of the enzyme will help in making Mpro non-functional in its role as a protease. The present project targets the dimeric interface of Mpro for finding suitable inhibitors using structure-based rational drug design approach. These potential inhibitory molecules will be tested further for their inhibitory activity against the action of Mpro using various biophysical and biochemical techniques. The identified anti-protease inhibitory molecules will be useful in the development of antiviral drugs for SARS-CoV-2.