Macrocyclic Peptidomimetics Forcing Peptides into Bioactive Conformations

Publisher Website
Google Scholar
Abstract
Cyclic peptides that are potent regulators of biological processes are rapidly emerging as important mechanistic probes and drug leads. Nature clearly uses macrocycles to. constrain peptides into conformations that can selectively bind proteins or. small molecules. Therapeutic effects of such macrocycles, often containing additional conformational constraints that fine­ tune structure (e.g. D-amino acids, N-methyl substituents, aromatic rings, to name a few), have so far been mainly discovered by accident. However it is now becoming possible to rationally design synthetic macrocycles to selectively recognize and inhibit a specific protein. A receptor-binding struc­ ture is more easily adopted by macrocyclic peptidomimetics than more flexible acyclic peptides because the former have less conformational entropy. Macrocycles are often stable to hydrolysis by peptidases that degrade acyclic peptides and hydrophobic side chains can protect peptide bonds in macrocycles from hydrolysis, as well as enhance lipophilicity, cell permeability and bioavailability. Synthetic efforts to obtain bioactive conformations of short peptides have so far been substrate-based, guided by molecular modelling predictions and structure-activity data for modified amino acid sequences of substrates. However, dramatic advances in molecular biology, X-ray crystallography, NMR spectroscopy and computing are rapidly producing three dimensional structures of proteins, promising direct observation of protein-bound conformations of small molecules and receptor-based design of peptidomimetics with surface complementarity for proteins. This perspective review highlights examples of both natural and synthetic bioactive macrocyclic peptides containing constraints that fix conformation, and briefly illustrates the promise that receptor-based design holds for structural and functional mimicry of peptides by macrocycles.

This publication has 0 references indexed in Scilit: