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Access Type
WSU Access
Date of Award
January 2024
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Biochemistry and Molecular Biology
First Advisor
Ladislau C. Kovari
Abstract
SARS-CoV-2, the virus responsible for COVID-19, poses an ongoing global health threat. Despite concerted efforts, containment remains elusive. To address this challenge, there is a pressing demand for drugs that utilize diverse mechanisms of action. In human coronaviruses (HCoV), the papain-like protease (PLpro) domain of Nsp3 is necessary for viral replication. Moreover, by interfering with host immunological responses by cleaving ubiquitin (Ub) and interferon-stimulated gene 15 protein (ISG-15) from host proteins, PLpro contributes to the "cytokine storm" linked to COVID-19. As a result, PLpro is a promising target for structure-based drug design. In this study, we have refined noncovalent and covalent inhibitors of SARS-CoV-2 PLpro from the primary literature, resulting in lead inhibitors with improved cytotoxicity and specificity while improving antiviral efficacy. We observe tight binding and engagement of the BL2 loop, BL2 groove, and Alpha cleft of PLpro, effectively obstructing the active site from natural substrates like ISG-15 and Ub. Studies on selectivity reveal very little off-target activity against the closest human structural homologs of PLpro. While there is high activity towards PLpro from SARS-CoV and SARS-CoV-2, it does not extend to MERS-CoV PLpro. These findings underscore the importance of investigating structurally diverse starting scaffolds for developing broad-spectrum HCoV PLpro inhibitors. These findings also expedite the structure-based design endeavors aimed at targeting PLpro to identify highly selective inhibitors with clinical significance.
Recommended Citation
Al-Homoudi, Abdullah Ibrahim, "Rational Design Of Novel Therapeutics Targeting Sars-Cov-2 Papain-Like Protease" (2024). Wayne State University Dissertations. 4012.
https://digitalcommons.wayne.edu/oa_dissertations/4012
