Targeting biomolecules with reversible covalent chemistry
Open accessAbstract
Interaction of biomolecules typically proceeds in a highly selective and reversible manner, for which covalent bond formation has been largely avoided due to the potential difficulty of dissociation. However, employing reversible covalent warheads in drug design has given rise to covalent enzyme inhibitors that serve as powerful therapeutics, as well as molecular probes with exquisite target selectivity. This review article summarizes the recent advances in the development of reversible covalent chemistry for biological and medicinal applications. Specifically, we document the chemical strategies that allow for reversible modification of the three major classes of nucleophiles in biology: thiols, alcohols and amines. Emphasis is given to the chemical mechanisms that underlie the development of these reversible covalent reactions and their utilization in biology.
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Nitriles are more reversible than acrylamides because thiol elimination from the thioimidate adduct is easy.
“the ease of thiol elimination from the thioimidate adduct makes nitriles more reversible than some other electrophiles, such as acrylamides104.”
From Advances in covalent drug discovery (2022) · cites this paper as [104]
Nitriles can covalently bind highly reactive nucleophiles.
“Nitriles can covalently bind particularly reactive nucleophiles; however, the ease of thiol elimination from the thioimidate adduct makes nitriles more reversible than some other electrophiles, such as acrylamides104.”
From Advances in covalent drug discovery (2022) · cites this paper as [104]
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- Authors
- Bandyopadhyay, A., & Gao, J.
- Affiliations
- Boston College (US)
- Corresponding author
- Gao, Jianmin
- Venue
- Current Opinion in Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 34
- Pages
- 110-116
- ISSN
- 1367-5931 (ISSN-L)
- PMC
- PMC5107367
- OpenAlex
- W2508430021
- Cited by
- 143
- References
- 40
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 14 · 2023: 25 · 2022: 13 · 2021: 21 · 2020: 11 · 2019: 14 · 2018: 9 · 2017: 7 · 2016: 1
- FWCI
- 0.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Current Opinion in Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (GM102735)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Physical Sciences › Materials Science › Polymers and Plastics › Polymer composites and self-healing
- Keywords
- covalent enzyme inhibitors, covalent drug design, biomolecule modification, thiol chemistry, alcohol chemistry, amine chemistry, molecular probes
- MeSH terms
- Acrylamides, Amines, Kinetics
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