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Structural Analysis of Inhibitor Binding to the Feline Enteric Coronavirus (FECV) Main Protease
Arooma Maryam1, Stephanie A Moquin2, Dustin Dovala2
1Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Abstract:
Coronaviruses include various strains that reside in natural animal reservoirs, with zoonotic transmission posing risks to both domesticated animals and human health. Recent efforts to address coronavirus infections have focused on developing inhibitors targeting the main protease (Mpro), some of which exhibit potential broad-spectrum efficacy. This study presents crystal structures of four clinically relevant inhibitors-GC376, PF-00835231, nirmatrelvir, and ibuzatrelvir-bound to Mpro from the feline coronavirus strain FECV-UU23. Structural analysis identified distinct FECV-specific features within the active site where these inhibitors bind and revealed S4 loop as a susceptible structural region essential for the enhanced binding of inhibitors in UU23 Mpro. We therefore propose to incorporate sterically constrained, functionally tailored heterocyclic moieties at the P3 site of known inhibitors which can optimally engage Q187, P188, and S189 residues of the S4 loop. The findings presented enhance understanding of inhibitor specificity and reinforce the promise of these inhibitor scaffolds for developing antivirals against feline coronavirus strains, with possible applications in broad-spectrum coronavirus therapy.
Insights
Researchers studied feline coronavirus main protease (Mpro) inhibitors, revealing unique binding site features. Tailoring inhibitors for the S4 loop could enhance efficacy against feline and other coronaviruses.
Area of Science:
- Structural Biology
- Virology
- Medicinal Chemistry
Background:
- Coronaviruses, including feline coronavirus (FECV), pose zoonotic risks.
- Inhibitors targeting the main protease (Mpro) show promise for broad-spectrum antiviral therapy.
- Understanding inhibitor-Mpro interactions is crucial for drug development.
Purpose of the Study:
- To elucidate the structural basis of inhibitor binding to FECV Mpro.
- To identify FECV-specific features influencing inhibitor efficacy.
- To propose strategies for optimizing existing Mpro inhibitors.
Main Methods:
- X-ray crystallography was used to determine the structures of four inhibitors (GC376, PF-00835231, nirmatrelvir, ibuzatrelvir) bound to FECV Mpro.
- Structural analysis focused on the Mpro active site and inhibitor interactions.
- Structure-activity relationships were investigated to guide inhibitor design.
Main Results:
- Distinct FECV-specific features were identified in the Mpro active site.
- The S4 loop was found to be a critical region for enhanced inhibitor binding.
- Specific interactions between inhibitors and FECV Mpro residues Q187, P188, and S189 were observed.
Conclusions:
- The study enhances understanding of inhibitor specificity for FECV Mpro.
- Tailoring inhibitors with specific heterocyclic moieties at the P3 site could optimize engagement with the S4 loop.
- Findings support the development of novel antivirals against feline coronaviruses and potentially other coronavirus strains.
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