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Solution, solid phase and computational structures of apicidin and its backbone-reduced analogs

Lookup NU author(s): Emeritus Professor Bill Clegg, Dr Mark Elsegood

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Abstract

The recently isolated broad-spectrum antiparasitic apicidin (1) is one of the few naturally occurring cyclic tetrapeptides (CTP). Depending on the solvent, the backbone of 1 exhibits two γ-turns (in CH2Cl2) or a β-turn (in DMSO), differing solely in the rotation of the plane of one of the amide bonds. In the X-ray crystal structure, the peptidic C=Os and NHs are on opposite sides of the backbone plane, giving rise to infinite stacks of cyclotetrapeptides connected by three intermolecular hydrogen bonds between the backbones. Conformational searches (Amber force field) on a truncated model system of 1 confirm all three backbone conformations to be low-energy states. The previously synthesized analogs of 1 containing a reduced amide bond exhibit the same backbone conformation as 1 in DMSO, which is confirmed further by the X-ray crystal structure of a model system of the desoxy analogs of 1. This similarity helps in explaining why the desoxy analogs retain some of the antiprotozoal activities of apicidin. The backbone-reduction approach designed to facilitate the cyclization step of the acyclic precursors of the CTPs seems to retain the conformational preferences of the parent peptide backbone, Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd.


Publication metadata

Author(s): Kranz M, Murray PJ, Taylor S, Upton RJ, Clegg W, Elsegood MRJ

Publication type: Article

Publication status: Published

Journal: Journal of Peptide Science

Year: 2006

Volume: 12

Issue: 6

Pages: 383-388

ISSN (print): 1075-2617

ISSN (electronic): 1099-1387

Publisher: John Wiley & Sons Ltd.

URL: http://dx.doi.org/10.1002/psc.738

DOI: 10.1002/psc.738

PubMed id: 16342331


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