Inhibition of the 3CL Protease of SARS-CoV-2 as a Promising Target for Antiviral Drug Treatment

Disciplines

Biochemistry

Abstract (300 words maximum)

In 2020, the global pandemic known as COVID-19, an infectious disease caused by severe acute respiratory syndrome – coronavirus 2 (SARS-CoV-2), sparked a race to find a suitable treatment for the rapidly spreading virus. SARS-CoV-2 contains single-stranded RNA with 14 open reading frames (ORFs). Two of these ORFs, 1a and 1b, encode for two replicase polyproteins: pp1a and pp1b. These polyproteins are cleaved by two proteases, known as papain-like (PL) and 3-chymotrypsin-like (3CL) proteases. The 3CL protease is the main protease of SARS-CoV-2, and plays a key role in viral protein replication. The protease contains a dyad of His41 and Cys145 that act as an active site to cleave polyproteins into smaller non-structural proteins (nsps). Antiviral drugs targeting the 3-chymotrypsin-like (3CL) protease of SARS-CoV-2 have been explored as a promising solution to combat coronavirus infections. Due to the 3CL protease showing similar properties to chymotrypsin, a serine protease, it is possible that chymotrypsin inhibitors could also inhibit the 3CL protease. In this theoretical study, three crystal structures of known serine protease inhibitors were investigated against the crystal structure of the SARS-CoV-2 3CL protease. Docking studies suggest that one inhibitor, R-elafin, appears to block access to the pocket containing the His41-Cys145 active site, showing potential inhibitory properties. Two other inhibitors will be studied to visualize the potential inhibition patterns on the 3CL protease. This study was completed through a CURE CHEM 3512L course. Throughout this course-based study, we applied our knowledge of protein inhibition to bioinformatics and structural biochemistry by visualizing crystal structures.

Academic department under which the project should be listed

CSM - Chemistry and Biochemistry

Primary Investigator (PI) Name

Rajnish Singh

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Inhibition of the 3CL Protease of SARS-CoV-2 as a Promising Target for Antiviral Drug Treatment

In 2020, the global pandemic known as COVID-19, an infectious disease caused by severe acute respiratory syndrome – coronavirus 2 (SARS-CoV-2), sparked a race to find a suitable treatment for the rapidly spreading virus. SARS-CoV-2 contains single-stranded RNA with 14 open reading frames (ORFs). Two of these ORFs, 1a and 1b, encode for two replicase polyproteins: pp1a and pp1b. These polyproteins are cleaved by two proteases, known as papain-like (PL) and 3-chymotrypsin-like (3CL) proteases. The 3CL protease is the main protease of SARS-CoV-2, and plays a key role in viral protein replication. The protease contains a dyad of His41 and Cys145 that act as an active site to cleave polyproteins into smaller non-structural proteins (nsps). Antiviral drugs targeting the 3-chymotrypsin-like (3CL) protease of SARS-CoV-2 have been explored as a promising solution to combat coronavirus infections. Due to the 3CL protease showing similar properties to chymotrypsin, a serine protease, it is possible that chymotrypsin inhibitors could also inhibit the 3CL protease. In this theoretical study, three crystal structures of known serine protease inhibitors were investigated against the crystal structure of the SARS-CoV-2 3CL protease. Docking studies suggest that one inhibitor, R-elafin, appears to block access to the pocket containing the His41-Cys145 active site, showing potential inhibitory properties. Two other inhibitors will be studied to visualize the potential inhibition patterns on the 3CL protease. This study was completed through a CURE CHEM 3512L course. Throughout this course-based study, we applied our knowledge of protein inhibition to bioinformatics and structural biochemistry by visualizing crystal structures.