Selective irreversible inhibition of a protease by targeting a noncatalytic cysteine
Abstract
Designing selective inhibitors of proteases has proven problematic, in part because pharmacophores that confer potency exploit the conserved catalytic apparatus. We developed a fundamentally different approach by designing irreversible inhibitors that target noncatalytic cysteines that are structurally unique to a target in a protein family. We have successfully applied this approach to the important therapeutic target HCV protease, which has broad implications for the design of other selective protease inhibitors.
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Covalent inhibitors can reduce dosage and improve compliance, avoiding some potential resistance mechanisms.
“At the same time, covalent inhibitors can also reduce dosage and improve compliance, avoiding some potential resistance mechanisms.33,34”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [34]
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References 21 · Cited by 95
- Authors
- Hagel, M., Niu, D., St Martin, T., Sheets, M. P., Qiao, L., Bernard, H., Karp, R. M., Zhu, Z., Labenski, M. T., Chaturvedi, P., Nacht, M., Westlin, W. F., Petter, R. C., & Singh, J.
- Affiliations
- Takeda Oncology (United States) (US)
- Corresponding author
- Singh, Juswinder
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2010-11-28
- Volume
- 7
- Issue
- 1
- Pages
- 22-24
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W2119177802
- Cited by
- 95
- References
- 21
- Citations by year
- 2026: 3 · 2024: 1 · 2023: 6 · 2022: 3 · 2021: 5 · 2020: 10 · 2019: 4 · 2018: 4 · 2017: 8 · 2016: 10 · 2015: 9 · 2014: 6 · 2013: 11 · 2012: 8
- FWCI
- 5.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatitis C virus research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- irreversible inhibitors, protease inhibitors, substrate binding pocket
- MeSH terms
- Biochemistry, Cysteine, Oligopeptides, Virology, Drug Design, Cysteine Proteinase Inhibitors, Hepacivirus, Crystallography, X-Ray, Biocatalysis
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