Thiazole-based γ-building blocks as reverse-turn mimetic to design a Gramicidin S analogue: Conformational and biological evaluation

Chemistry – A European Journal, 2013, Volume: 20, Issue: 22, Pages: 6713-6720, DOI: 10.1002/chem.201402190

B. Legrand, L. Mathieu, A. Lebrun, S. Andriamanarivo, V. Lisowski, N. Masurier, S. Zirah, Y. Kang, J. Martinez, L. Maillard


This paper describes the ability of a new class of heterocyclic γ-amino acids named ATCs (4-amino(methyl)-1,3-thiazole-5-carboxylic acids) to induce turns when included in a tetrapeptide template.  Both hybrid Ac-Val-(R or S)-ATC-Ile-Ala-NH2 sequences were synthesized and their conformations were studied by CD, NMR spectroscopy, MD simulations, and DFT calcns.  It was demonstrated that the ATCs induced highly stable C9 pseudocycles in both compds. promoting a twist turn and a reverse turn conformation depending on their abs. configurations.  As a proof of concept, a bioactive analog of gramicidin S was successfully designed using an ATC building block as a turn inducer.  The NMR soln. structure of the analog adopted an antiparallel β-pleated sheet conformation similar to that of the natural compd.  The hybrid α,γ-cyclopeptide exhibited significant reduced hemotoxicity compared to gramicidin S, while maintaining strong antibacterial activity.