Peptides and peptidomimetics as regulators of protein–protein interactions

Abstract

Protein-protein interactions are essential for almost all intracellular and extracellular biological processes. Regulation of protein-protein interactions is one strategy to regulate cell fate in a highly selective manner. Specifically, peptides are ideal candidates for inhibition of protein-protein interactions because they can mimic a protein surface to effectively compete for binding. Additionally, peptides are synthetically accessible and can be stabilized by chemical modifications. In this review, we survey screening and rational design methods for identifying peptides to inhibit protein-protein interactions, as well as methods for stabilizing peptides to effectively mimic protein surfaces. In addition, we discuss recent applications of peptides to regulate protein-protein interactions for both basic research and therapeutic purposes.

‘À La Carte’ Cyclic Hexapeptides: Fine Tuning Conformational Diversity while Preserving the Peptide Scaffold.

“…More challenging, however, is the design of molecules with the ability to bind to the solvent‐exposed protein surface and specifically recognize the large interfacial areas involved in protein‐protein interactions, with the purpose of interfering in the functional activity of the target protein . The growing appreciation that these complex protein‐protein interfaces appear to be ‘undruggable’ by small ligands has coincided with renewed interest in macrocycles, and cyclic peptides in particular, as potential protein binders, based on the premise that these cyclic molecules may be more suited to mimic natural biorecognition processes …”

Small‐Molecule Activators of Glucose‐6‐phosphate Dehydrogenase (G6PD) Bridging the Dimer Interface

“…[3] However,t argeting PPIs with smallm olecules has long been considered ac hallenging area for drug discovery largely outside the realm of the druggable genome. [5,6] Efforts focusedo nm odulating PPIs have almost entirely centered aroundt he inhibition of these interactions, [7] but an umber of natural products and designed ligands derive clinicalu tility from promoting the interaction of two or more proteins. [5,6] Efforts focusedo nm odulating PPIs have almost entirely centered aroundt he inhibition of these interactions, [7] but an umber of natural products and designed ligands derive clinicalu tility from promoting the interaction of two or more proteins.…”

“…[4] Yet, an umber of methods such as fragment-basedd rug discovery (FBDD) and rational peptided esignh ave produced leads with translational potential. [5,6] Efforts focusedo nm odulating PPIs have almost entirely centered aroundt he inhibition of these interactions, [7] but an umber of natural products and designed ligands derive clinicalu tility from promoting the interaction of two or more proteins. [8] G6PD, an ancientm etabolic enzymep resenti ne ukaryotes and prokaryotes, catalyzes the first step of the pentose phosphate pathway (PPP).…”

Peptide modulators of Rac1/Tiam1 protein‐protein interaction: An alternative approach for cardiovascular diseases

“…In particular, the insertion of an unnatural alpha, alpha disubstituted amino acid, that is norbornane amino acid, and the side chain stapling have been evaluated as strategies to obtain engineered peptides. Indeed, these approaches might lead to peptides that are stable to metabolism, inherently stable to proteases and peptidases, and can fold into well‐ordered secondary structures …”