Conformationally homogeneous cyclic tetrapeptides: useful new three-dimensional scaffolds.
The most commonly recognized motifs in protein-protein interactions are gamma and beta turns, which are defined by three to four contiguous amino acids in a peptide sequence. Cyclic tetrapeptides thus represent minimalist turn mimetics, but their usefulness is compromised by strain in their 12-membered rings, making them difficult to cyclize, unstable to hydrolysis/metabolism, and conformationally heterogeneous in polar solvents. Appropriate placement of a beta amino acid in a tetrapeptide creates a 13-membered ring that is shown to be easier to cyclize, hydrolytically more stable, and conformationally homogeneous in polar solvents such as DMSO and water. Three-dimensional structures reveal that these cyclic tetrapeptides are novel rigid scaffolds, their unique side-chain projections matching a structurally diverse range of useful nonpeptidic templates, including sugars and spirocyclic compounds, found as components of natural products. The results provide a potentially useful link between protein architecture and organic natural products. On the basis of protein turn sequences (not protein structures) alone simple cyclic tetrapeptide libraries with a beta amino acid can be rationally designed as conformationally restricted, easily synthesized, and stereochemically controlled screening tools for rapidly identifying pharmacophore space that can then be computer-matched to more complex known natural product templates for drug development.
Glenn
Matthew P
MP
Centre for Drug Design and Development, Institute for Molecular Bioscience, University of Queensland, Brisbane Qld 4072, Australia.
Kelso
Michael J
MJ
Tyndall
Joel D A
JD
Fairlie
David P
DP
D000613:Aminobutyrates / Q000737:chemistry*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013816:Thermodynamics
D000613:Aminobutyrates; D009842:Oligopeptides; D010456:Peptides, Cyclic; C014328:2-amino-4-phenylbutyric acid