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‘À La Carte’ Cyclic Hexapeptides: Fine Tuning Conformational Diversity while Preserving the Peptide Scaffold.
Author(s) -
Ciudad Sonia,
BayóPuxán Núria,
Varese Monica,
Seco Jesús,
Teixidó Meritxell,
García Jesús,
Giralt Ernest
Publication year - 2018
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201800254
Subject(s) - cyclic peptide , chemistry , peptide , serine , alanine , tryptophan , chirality (physics) , peptide bond , protein structure , arginine , conformational change , peptide conformation , amino acid , stereochemistry , biochemistry , physics , phosphorylation , chiral symmetry breaking , quantum mechanics , nambu–jona lasinio model , quark
Cyclic peptides have recently emerged as promising modulators of challenging protein‐protein interactions. Here we report on the design, synthesis and conformational behavior of a small library composed of C2 symmetric cyclic hexapeptides of type c(Xaa‐D‐Pro‐Yaa) 2 , where Xaa and Yaa are chosen from alanine, isoleucine, serine, glutamic acid, arginine and tryptophan due to the favorable properties of the side chains of these residues to recognize complex protein surfaces. We used a combination of nuclear magnetic resonance and molecular dynamic simulations to perform an extensive conformational analysis of a representative set of cyclic hexapeptides. Our results indicated that both the chemical nature and the chirality of the variable Xaa and Yaa positions play an important role in the cis/trans configuration of the Xaa‐D‐Pro bonds and in the conformational preferences of this family of peptides. This structural tuning can be exploited in design strategies seeking to optimize the binding efficiency and selectivity of cyclic hexapeptides towards protein surfaces.