ArticleProceedings of the National Academy of Sciences of the United States of America2020
Systematic identification of engineered methionines and oxaziridines for efficient, stable, and site-specific antibody bioconjugation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 57 citations in OpenAlex.
- Tryptophan Bioconjugation through Auxiliary Boron-Accelerated, Additive-Free Friedel-Crafts Alkylation.JACS Au · 2026Article
- A Modular and Convergent "Stick and Click" Conjugation Platform Enables Fast Antibody Conjugate Library Synthesis.Bioconjugate chemistry · 2026Article
- Incorporation of azide groups into an engineered Fn3 scaffold protein for site-specific, bioorthogonal conjugation.Protein engineering, design & selection : PEDS · 2026Article
- Site-specific labelling of native peptides and proteins: chemical and enzymatic strategies.Beilstein journal of organic chemistry · 2026Review
- Exploiting thioether reactivity to label mycobacterial glycans.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Emerging opportunities for intact and native protein analysis using chemical proteomics.Analytica chimica acta · 2025Review
- Light-Activated Reactivity of Nitrones with Amino Acids and Proteins.Angewandte Chemie (International ed. in English) · 2025Article
- Multiscale photocatalytic proximity labeling reveals cell surface neighbors on and between cells.Science (New York, N.Y.) · 2024Article
- Ultrafast Au(III)-Mediated Arylation of Cysteine.Journal of the American Chemical Society · 2024Article
- Article
- Photoproximity Labeling from Single Catalyst Sites Allows Calibration and Increased Resolution for Carbene Labeling of Protein Partners In Vitro and on Cells.ACS central science · 2024Article
- Site-SpecificBioconjugate chemistry · 2023Article
- Chemoselective Methionine Labelling of Recombinant Trastuzumab Shows High In Vitro and In Vivo Tumour Targeting.Chemistry (Weinheim an der Bergstrasse, Germany) · 2023Article
- An Activity-Based Oxaziridine Platform for Identifying and Developing Covalent Ligands for Functional Allosteric Methionine Sites: Redox-Dependent Inhibition of Cyclin-Dependent Kinase 4.Journal of the American Chemical Society · 2022Article
- Chemical Conjugation to Less Targeted Proteinogenic Amino Acids.Chembiochem : a European journal of chemical biology · 2022Review
- Multivalent ACE2 engineering-A promising pathway for advanced coronavirus nanomedicine development.Nano today · 2022Review
- Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis.Molecular cell · 2022Article
- Biomolecule-Compatible Dehydrogenative Chan-Lam Coupling of Free Sulfilimines.Journal of the American Chemical Society · 2022Article
- Are Methionine Sulfoxide-Containing Proteins Related to Seed Longevity? A Case Study ofPlants (Basel, Switzerland) · 2022Article
- Targeting a proteolytic neoepitope on CUB domain containing protein 1 (CDCP1) for RAS-driven cancers.The Journal of clinical investigation · 2022Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
The field of chemical modification of proteins has been dominated by random modification of lysines or more site-specific labeling of cysteines, each with attendant challenges. Recently, we have developed oxaziridine chemistry for highly selective modification of methionine called redox-activated chemical tagging (ReACT) but have not broadly tested the molecular parameters for efficient and stable protein modification. Here we systematically scanned methionines throughout one of the most popular antibody scaffolds, trastuzumab, used for antibody engineering and drug conjugation. We tested the expression, reactivities, and stabilities of 123 single engineered methionines distributed over the surface of the antibody when reacted with oxaziridine. We found uniformly high expression for these mutants and excellent reaction efficiencies with a panel of oxaziridines. Remarkably, the stability to hydrolysis of the sulfimide varied more than 10-fold depending on temperature and the site of the engineered methionine. Interestingly, the most stable and reactive sites were those that were partially buried, presumably because of their reduced access to water. There was also a 10-fold variation in stability depending on the nature of the oxaziridine, which was determined to be inversely correlated with the electrophilic nature of the sulfimide. Importantly, the stabilities of the best analogs were sufficient to support their use as antibody drug conjugates and potent in a breast cancer mouse xenograft model over a month. These studies provide key parameters for broad application of ReACT for efficient, stable, and site-specific antibody and protein bioconjugation to native or engineered methionines.
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