Targeting protein-protein interfaces using macrocyclic peptides

Abstract

Protein-protein interactions (PPIs) are critical in numerous biological processes including signaling transduction, function regulations, and disease development. To regulate PPIs has been thought to be challenging due to their highly dynamic and expansive interfacial areas. Nonetheless, successful examples have been reported of targeting PPIs using small molecules, peptides, and proteins. Peptides, especially macrocyclic peptides have proven to be a particularly useful tool to inhibit PPIs for their exquisite potency, stability and selectivity. Herein we review the recent developments of this area of research, focusing on the macrocyclic peptides isolated from natural products, identified from library screening, and rationally designed based on structures, as PPI regulators.

Keywords: inhibitor; macrocyclic peptide; protein−protein interface; rational design.

Figure 1

Cyclic peptides are more rigid than their linear counterparts upon binding to proteins, leading to more potent inhibitors of PPIs.

Figure 2

The chemical structures of macrocyclic peptide agonist, A, and antagonist, B, of protein-protein interactions.