Thia-Michael Stapling of Allenamide-Incorporated α-Helical Antimicrobial Peptides.

Authors

Tae-Ung Na, Shannon Macdonald, Polly Chuanrong Sun, Margaret A Brimble, Thomas K Proft, Catherine J Tsai, Alan J Cameron

Published in

The Journal of organic chemistry. Jul 02, 2026. Epub Jul 02, 2026.

Abstract

Herein is presented a chemoselective thia-Michael stapling approach, mediated by a highly electrophilic allenamide group, occurring spontaneously in a mixture of aqueous buffer and 2,2,2-trifluoroethanol (TFE). Leveraging the commercially available homologs of Lys and Cys, the staple length and stereochemistry are readily interchangeable, presenting a facile strategy to introduce i, i + 3, i, i + 4 and i, i + 7 conformational constraints to α-helical peptides. Harnessing this approach, a number of stapled antimicrobial peptides (StAMPs) were prepared from amphibian-derived defense peptides. A stapled temporin-1Ta analog demonstrated markedly improved helicity, enhanced potency toward Gram-positive pathogens, and low cytotoxicity toward mammalian cells. This StAMP was further demonstrated to be well-tolerated and possess in vivo efficacy toward lethal and sublethal Streptococcus pyogenes in vivo infection models in the wax worm, Galleria mellonella.

PMID:
42391562
Bibliographic data and abstract were imported from PubMed on 03 Jul 2026.

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