Condensation of 2-((Alkylthio)(aryl)methylene)malononitrile with 1,2-Aminothiol as a novel bioorthogonal reaction for site-specific protein modification and peptide cyclization

Zheng, Xiaoli, Li, Zhuoru, Gao, Wei, Meng, Xiaoting, Li, Xuefei, Luk, Louis Y. P. ORCID: https://orcid.org/0000-0002-7864-6261, Zhao, Yibing, Tsai, Yu-Hsuan ORCID: https://orcid.org/0000-0003-0589-5088 and Wu, Chuanliu 2020. Condensation of 2-((Alkylthio)(aryl)methylene)malononitrile with 1,2-Aminothiol as a novel bioorthogonal reaction for site-specific protein modification and peptide cyclization. Journal of the American Chemical Society 142 (11) , pp. 5097-5103. 10.1021/jacs.9b11875

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Abstract

Site-specific modification of peptides and proteins has wide applications in probing and perturbing biological systems. Herein we report that 1,2-aminothiol can react rapidly, specifically and efficiently with 2-((alkylthio)(aryl)methylene)malononitrile (TAMM) under biocompatible conditions. This reaction undergoes a unique mechanism involving thiol-vinyl sulfide exchange, cyclization, and elimination of dicyanomethanide to form 2-aryl-4,5-dihydrothiazole (ADT) as a stable product. An 1,2-aminothiol functionality can be introduced into a peptide or a protein as an N-terminal cysteine or an unnatural amino acid. The bioorthogonality of this reaction was demonstrated by site-specific labeling of not only synthetic peptides and a purified recombinant protein but also proteins on mammalian cells and phages. Unlike other reagents in bioorthogonal reactions, the chemical and physical properties of TAMM can be easily tuned. TAMM can also be applied to generate phage-based ADT-cyclic peptide libraries without reducing phage infectivity. Using this approach, we identified ADT-cyclic peptides with high affinity to different protein targets, providing valuable tools for biological studies and potential therapeutics. Furthermore, the mild reaction conditions of TAMM condensation warrant its use with other bioorthogonal reactions to simultaneously achieve multiple site-specific modifications.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Chemistry
Publisher:	American Chemical Society
ISSN:	0002-7863
Funders:	Royal Society
Date of First Compliant Deposit:	13 March 2020
Date of Acceptance:	28 February 2020
Last Modified:	17 Nov 2024 13:45
URI:	https://orca.cardiff.ac.uk/id/eprint/130394

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