The role of N-methyl squaramides in a hydrogen-bonding strategy to fold peptidomimetic compounds

Abstract

[eng] Small peptides and peptomimetic compounds are valuable tools to probe and study biological systems. Small synthetic peptide analogues adopt a given secondary structure driven by structural modules that organize the compound architecture. Among them, b- and a-turn mimetics are widely used. This work reports SQ4 and SQ5 squaramido-based turn modules that combine tertiary and secondary squaramide bonds in their structure to control their confor- mational properties. The efficacy of this combination has been evaluated to promote folding in peptide-like compounds to obtain parallel and antiparallel-hairpin model compounds in hydrogen-bonding competitive media. Crystallographic structures of model compounds and conformational studies based on NMR spectroscopic analysis of the squaramido-peptides confirm that secondary-tertiary squaramides are more prone to adopt the E,Z-conformation than di-secondary squaramides, and consequently are more suitable to gain conformational control over foldable peptidomimetic compounds.