Thiazole-Based γ-Building Blocks as Reverse-Turn Mimetic to Design a Gramicidin S Analogue: Conformational and Biological Evaluation
2014
This paper describes the ability of a new class of heterocyclic g-amino acids named ATCs (4-amino(methyl)- 1,3-thiazole-5-carboxylic acids) to induce turns when includ- ed in a tetrapeptide template. Both hybrid Ac-Val-(R or S)- ATC-Ile-Ala-NH2 sequences were synthesized and their con- formations were studied by circular dichroism, NMR spec- troscopy, MD simulations, and DFT calculations. It was dem- onstrated that the ATCs induced highly stable C9 pseudo- cycles in both compounds promoting a twist turn and a re- verse turn conformation depending on their absolute config- urations. As a proof of concept, a bioactive analogue of gra- micidin S was successfully designed using an ATC building block as a turn inducer. The NMR solution structure of the analogue adopted an antiparallel b-pleated sheet conforma- tion similar to that of the natural compound. The hybrid a,g- cyclopeptide exhibited significant reduced haemotoxicity compared to gramicidin S, while maintaining strong antibac- terial activity.
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