Deciphering the Molecular Mechanism of HCV Protease Inhibitor Fluorination as a General Approach to Avoid Drug Resistance [preprint]
Authors
Zephyr, JacquetoDesaboini, Nageswara Rao
Vo, Sang V.
Henes, Mina
Kosovrasti, Klajdi
Matthew, Ashley N.
Hedger, Adam K
Timm, Jennifer
Chan, Elise T.
Ali, Akbar
Yilmaz, Nese Kurt
Schiffer, Celia A.
UMass Chan Affiliations
Morningside Graduate School of Biomedical SciencesDepartment of Biochemistry and Molecular Pharmacology
Document Type
PreprintPublication Date
2021-11-30Keywords
X-ray crystallographyProtease inhibitors
Structure-based drug design
Structural biology
Medicinal chemistry
Biochemistry
Enzymes and Coenzymes
Medicinal-Pharmaceutical Chemistry
Molecular Biology
Structural Biology
Metadata
Show full item recordAbstract
Third generation Hepatitis C virus (HCV) NS3/4A protease inhibitors (PIs), glecaprevir and voxilaprevir, are highly effective across genotypes and against many resistant variants. Unlike earlier PIs, these compounds have fluorine substitutions on the P2-P4 macrocycle and P1 moieties. Fluorination has long been used in medicinal chemistry as a strategy to improve physicochemical properties and potency. However, the molecular basis by which fluorination improves potency and resistance profile of HCV NS3/4A PIs is not well understood. To systematically analyze the contribution of fluorine substitutions to inhibitor potency and resistance profile, we used a multi-disciplinary approach involving inhibitor design and synthesis, enzyme inhibition assays, co-crystallography, and structural analysis. A panel of inhibitors in matched pairs were designed with and without P4 cap fluorination, tested against WT protease and the D168A resistant variant, and a total of 22 high-resolution co-crystal structures were determined. While fluorination did not significantly improve potency against the WT protease, PIs with fluorinated P4 caps retained much better potency against the D168A protease variant. Detailed analysis of the co-crystal structures revealed that PIs with fluorinated P4 caps can sample alternate binding conformations that enable adapting to structural changes induced by the D168A substitution. Our results elucidate molecular mechanisms of fluorine-specific inhibitor interactions that can be leveraged in avoiding drug resistance.Source
bioRxiv 2021.11.30.470632; doi: https://doi.org/10.1101/2021.11.30.470632. Link to preprint on bioRxiv.
DOI
10.1101/2021.11.30.470632Permanent Link to this Item
http://hdl.handle.net/20.500.14038/30740Notes
This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.
Related Resources
Now published in Journal of Molecular Biology doi: 10.1016/j.jmb.2022.167503
Rights
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1101/2021.11.30.470632
Scopus Count
Except where otherwise noted, this item's license is described as The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.