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A Physical Organic Approach to Tuning Reagents for Selective and Stable Methionine Bioconjugation

Christian, Alec H, Jia, Shang, Zhang, Patricia, Tena Meza, Arismel, Sigman, Matthew S, Chang, Christopher J and Toste, F Dean (2019) A Physical Organic Approach to Tuning Reagents for Selective and Stable Methionine Bioconjugation. Journal of the American Chemical Society JACS., 141 (32). pp. 12657-12662. ISSN 0002-78631520-5126


We report a data-driven, physical organic approach to the development of new methionine-selective bioconjugation reagents with tunable adduct stabilities. Statistical modeling of structural features described by intrinsic physical organic parameters was applied to the development of a predictive model and to gain insight into features driving stability of adducts formed from the chemoselective coupling of oxaziridine and methionine thioether partners through Redox Activated Chemical Tagging (ReACT). From these analyses, a correlation between sulfimide stabilities and sulfimide n (C=O) stretching frequencies was revealed. We exploited the rational gains in adduct stability exposed by this analysis to achieve the design and synthesis of a bis-oxaziridine reagent for peptide stapling. Indeed, we observed that a macrocyclic peptide formed by ReACT stapling at methionine exhibited improved uptake into live cells compared to an unstapled congener, highlighting the potential utility of this new \chemical tool for thioether modification. This work
provides a template for the broader use of data-driven approaches to bioconjugation chemistry and other chemical biology applications.

Item Type: Article
Date Deposited: 29 Oct 2019 00:45
Last Modified: 29 Oct 2019 00:45