Chemoselective small molecules that covalently modify one lysine in a non-enzyme protein in plasma
Open accessAbstract
A small molecule that could bind selectively to and then react chemoselectively with a non-enzyme protein in a complex biological fluid, such as blood, could have numerous practical applications. Herein, we report a family of designed stilbenes that selectively and covalently modify the prominent plasma protein transthyretin in preference to more than 4,000 other human plasma proteins. They react chemoselectively with only one of eight lysine e-amino groups within transthyretin. The crystal structure confirms the expected binding orientation of the stilbene substructure and the anticipated conjugating amide bond. These covalent transthyretin kinetic stabilizers exhibit superior amyloid inhibition potency compared to their noncovalent counterparts, and they prevent cytotoxicity associated with amyloidogenesis. Though there are a few prodrugs that, upon metabolic activation, react with a cysteine residue inactivating a specific non-enzyme, we are unaware of designed small molecules that react with one lysine e-amine within a specific non-enzyme protein in a complex biological fluid.
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Whether inhibitors are covalent or non-covalent, side effects arising from idiosyncratic risks are always an issue that has to be considered in drug research and development.
“Meanwhile, whether inhibitors are covalent or non-covalent, side effects arising from idiosyncratic risks are always an issue that has to be considered in drug research and development [46, 47].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [46]
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References 52 · Cited by 90
- Authors
- Choi, S., Connelly, S., Reixach, N., Wilson, I. A., & Kelly, J. W.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Kelly, Jeffery W
- Venue
- Nature Chemical Biology
- Published
- 2009-12-20
- Volume
- 6
- Issue
- 2
- Pages
- 133-139
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC3107129
- OpenAlex
- W2091920457
- Cited by
- 90
- References
- 52
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 8 · 2023: 2 · 2022: 8 · 2021: 6 · 2020: 7 · 2019: 9 · 2018: 6 · 2017: 7 · 2016: 3 · 2015: 3 · 2014: 3 · 2013: 3 · 2012: 4
- FWCI
- 2.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA058896)
- National Institute of Allergy and Infectious Diseases (R37AI042266, R01AI042266)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK046335, R01DK046335)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Amyloidosis: Diagnosis, Treatment, Outcomes
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Keywords
- prealbumin, lysine epsilon-amino group, stilbenes, amyloid fibril formation inhibition, plasma proteins, protein-ligand binding, crystal structure, prodrugs
- MeSH terms
- Cell Survival, Humans, Kinetics, Lysine, Models, Molecular, Prealbumin, Stilbenes, Drug Design, Protein Structure, Tertiary, Crystallography, X-Ray, Cell Line, Tumor, Protein Multimerization
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