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

preprint
submitted on 23.05.2019 and posted on 24.05.2019 by Alec Christian, Shang Jia, Patricia Zhang, Arismel Tena Meza, Matthew S. Sigman, Christopher Chang, F. Dean Toste
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  (C=O) stretching frequencies was revealed. We ex-ploited 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 unique 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.

Funding

DGE 1106400

ES004705

GM121383

NIH S10OD023532

History

Email Address of Submitting Author

alec.christian@berkeley.edu

Institution

University of California - Berkeley

Country

United States

ORCID For Submitting Author

0000-0002-7032-230X

Declaration of Conflict of Interest

None

Exports