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Access Type

WSU Access

Date of Award

January 2025

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Biochemistry and Molecular Biology

First Advisor

Ladislau C. Kovari

Abstract

Public health responses to COVID-19 have taken a two-pronged approach, utilizing both prophylactic vaccines for prevention and therapeutic antivirals for intervention. Targeting the SARS-CoV-2 main protease (3CLpro/Mpro), a protein essential for viral polyprotein processing and, thus, replication and propagation, presents a promising avenue for antiviral drug development. Our research focuses on the design of second-generation direct-acting antiviral agents that inhibit this protease. Employing a combination of X-ray crystallography, computational techniques, and biochemical assays, we have identified potent lead molecules targeting the SARS-CoV-2 3CLpro, expanding the battery of inhibitors available to treat coronavirus infection. We report the design of inhibitors with nanomolar potency against SARS-CoV-2 3CLpro, supported by high-resolution co-crystal structures of the inhibitor-enzyme complexes, in silico docking analysis, in vitro biochemical data. We also report the development of in silico screens that have successfully identified potent SARS-CoV-2 3CLpro inhibitors and the development of compounds that inhibit SARS-CoV-2 3CLpro nirmatrelvir and ensitrelvir-resistant mutants. These findings pave the way to position our inhibitors as strong candidates for further development in the fight against COVID-19.

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