期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 149, 期 -, 页码 193-210出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.02.057
关键词
Gramicidin; Azaproline foldamers; Antibiotic; RBC hemolysis; Liposomes and beta-helices
资金
- Division of Biology and Biological Sciences at Washington University
- Washington University Career Center
- Department of Biochemistry and Molecular Biophysics, WUSM
- Wellcome Trust (UK)
- University of Queensland (Australia)
Gramicidin A, a topical antibiotic made from alternating L and D amino acids, is characterized by its wide central pore; upon insertion into membranes, it forms channels that disrupts ion gradients. We present helical peptidomimetics with this characteristic wide central pore that have been designed to mimic gramicidin A channels. Mimetics were designed using molecular modeling focused on oligomers of heterochiral dipeptides of proline analogs, in particular azaproline (AzPro). Molecular Dynamics simulations in water confirmed the stability of the designed helices. A sixteen-residue Formyl-(AzPro-Pro)(8)-NHCH2CH2OH helix was synthesized as well as a full thirty-two residue Cbz-(AzPro-Pro)(16)-(OBu)-Bu-t channels. No liposomal lysis activity was observed suggesting lack of channel formation, possibly due to inappropriate hydrogen-bonding interactions in the membrane. These peptidomimetics also did not hemolyze red blood cells, unlike gramicidin A. (C) 2018 Elsevier Masson SAS. All rights reserved.
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