Thiazole-Based [gamma]-Building Blocks as Reverse-Turn Mimetic to Design a GramicidinS Analogue: Conformational and Biological Evaluation

This paper describes the ability of a new class of heterocyclic [gamma]-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 we...

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Veröffentlicht in:Chemistry : a European journal 2014-05, Vol.20 (22), p.6713-6720
Hauptverfasser: Legrand, Baptiste, Mathieu, Loïc, Lebrun, Aurélien, Andriamanarivo, Soahary, Lisowski, Vincent, Masurier, Nicolas, Zirah, Séverine, Kang, Young Kee, Martinez, Jean, Maillard, Ludovic T
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Sprache:eng
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Zusammenfassung:This paper describes the ability of a new class of heterocyclic [gamma]-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 gramicidinS was successfully designed using an ATC building block as a turn inducer. The NMR solution structure of the analogue adopted an antiparallel [beta]-pleated sheet conformation similar to that of the natural compound. The hybrid [alpha],[gamma]-cyclopeptide exhibited significant reduced haemotoxicity compared to gramicidinS, while maintaining strong antibacterial activity. [PUBLICATION ABSTRACT]
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201402190