Abstract

New therapeutics are needed to combat emerging viral diseases. In this presentation, I will discuss efforts led by ORNL to design covalent inhibitors that target the papain-like protease (PLpro) of SARS-CoV-2, the virus that causes the COVID-19 disease. Proteases are enzymes that break down polypeptides – compounds consisting of two or more amino acids linked in a chain. PLpro cuts viral polypeptides at specific places to generate the individual proteins that are required for viral replication. In addition, PLpro cuts human proteins involved in cellular signaling, which disrupts the immune system. As a result, PLpro is a promising target for antiviral drug discovery. 

We used a structure-based drug design approach, in which a previously determined X-ray crystal structure of an inhibitor bound to the protein was used to guide the design of improved inhibitors. Our most promising inhibitor prevents viral replication in mammalian cell lines, and X-ray crystallography confirmed its predicted binding mode. These findings present an opportunity for further development of PLpro inhibitors. 

This project involved researchers from five national labs, four universities and one biotech company. In ongoing work, our efforts are focused on developing similar compounds with increased antiviral efficacy, metabolic stability, and more favorable pharmacokinetic properties.

Biographical Sketch

Dr. Jerry Parks is the Group Leader for Molecular Biophysics in the Biosciences Division at Oak Ridge National Laboratory. He received his Ph.D. in chemistry from Duke University. He is a computational chemist by training and is interested in using various computational approaches to understand the structure, function and mechanism of proteins and enzymes.

Parks was previously involved in a landmark study published in the prestigious journal Science that identified two genes in bacteria responsible for transforming inorganic mercury into toxic methylmercury. This organic mercury produced in lakes and streams is taken up by fish. It can harm humans who eat lots of fish. The research solved a microbial mystery that had stumped scientists for decades.