Thiazole‐Based γ‐Building Blocks as Reverse‐Turn Mimetic to Design a Gramicidin S Analogue: Conformational and Biological Evaluation |
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| Authors: | Dr Baptiste Legrand Loïc Mathieu Aurélien Lebrun Soahary Andriamanarivo Prof Vincent Lisowski Dr Nicolas Masurier Dr Séverine Zirah Prof Young Kee Kang Prof Jean Martinez Dr Ludovic T Maillard |
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| Institution: | 1. Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Universités Montpellier I et II, UFR des Sciences Pharmaceutiques et Biologiques, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5 (France), Fax: (+33)?4‐67‐54‐86‐54;2. Muséum National d'Histoire Naturelle (MNHN), UMR 7245 CNRS/MNHN, Molécules de Communication et Adaptation des Micro‐organismes (MCAM), 57, rue Cuvier, 75005 Paris (France);3. Department of Chemistry and BK21 PLUS Research Team, Chungbuk National University, Cheongju, Chungbuk 361‐763 (Republic of Korea) |
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| Abstract: | 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 circular dichroism, NMR spectroscopy, MD simulations, and DFT calculations. It was demonstrated that the ATCs induced highly stable C9 pseudocycles in both compounds promoting a twist turn and a reverse turn conformation depending on their absolute configurations. As a proof of concept, a bioactive analogue of gramicidin S was successfully designed using an ATC building block as a turn inducer. The NMR solution structure of the analogue adopted an antiparallel β‐pleated sheet conformation similar to that of the natural compound. The hybrid α,γ‐cyclopeptide exhibited significant reduced haemotoxicity compared to gramicidin S, while maintaining strong antibacterial activity. |
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| Keywords: | amino acids gramicidin S hybrid peptide thiazoles |
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