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Solution, solid phase and computational structures of apicidin and its backbone‐reduced analogs
Author(s) -
Kranz Michael,
Murray Peter John,
Taylor Stephen,
Upton Richard J.,
Clegg William,
Elsegood Mark R. J.
Publication year - 2006
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.738
Subject(s) - chemistry , hydrogen bond , amide , peptide bond , stereochemistry , cyclic peptide , peptide , side chain , intermolecular force , crystal structure , crystallography , molecule , organic chemistry , polymer , biochemistry
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 CH 2 Cl 2 ) 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 COs 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.