Macrocycles as protein–protein interaction inhibitors

Abstract

Macrocyclic compounds such as cyclic peptides have emerged as a new and exciting class of drug candidates for inhibition of intracellular protein-protein interactions, which are challenging targets for conventional drug modalities (i.e. small molecules and proteins). Over the past decade, several complementary technologies have been developed to synthesize macrocycle libraries and screen them for binding to therapeutically relevant targets. Two different approaches have also been explored to increase the membrane permeability of cyclic peptides. In this review, we discuss these methods and their applications in the discovery of macrocyclic compounds against protein-protein interactions.

Second-generation DNA-templated macrocycle libraries for the discovery of bioactive small molecules

“…Macrocycles are generally known to display better stability in vivo than their linear counterparts 27, 30 , and to offer a balance between flexibility and pre-organization that allows macrocycles to interact across extended protein binding sites with entropic penalties that are lower than corresponding linear molecules. The latter feature renders them promising in targeting surfaces or protein-protein interactions, which can be difficult to target with conventional small-molecules libraries 31, 32 . Indeed, approximately 70 macrocyclic drugs have already been approved for human use and more than 35 macrocycles are in various stages of clinical development 33 .…”

Designed Macrocyclic Peptides as Nanomolar Amyloid Inhibitors Based on Minimal Recognition Elements

“…Blood-brain-barrier (BBB) crossing is ah ighly desirable property for drug candidates targeting the amyloid cascade in AD.However,the highly restrictive nature of the BBB allows for only very few neuropharmaceuticals to be delivered to the brain. [3] Thus,w en ext studied whether N-terminally fluorescein-labeled 2e (Fluos-2 e) could cross the BBB by using aw ell-established cell model of human cerebral microvascular endothelial cells (hCMECs) grown as confluent monolayers on Transwell membranes. [3] Thus,w en ext studied whether N-terminally fluorescein-labeled 2e (Fluos-2 e) could cross the BBB by using aw ell-established cell model of human cerebral microvascular endothelial cells (hCMECs) grown as confluent monolayers on Transwell membranes.…”

“…[2] Importantly,n one of the reported inhibitors of amyloid selfassembly of Ab40(42) or IAPP has yet advanced to the clinic. [2,3] Alarge number of peptide-based inhibitors of Ab40(42) or IAPP amyloidogenesis has been derived from their target polypeptides. [2,3] Alarge number of peptide-based inhibitors of Ab40(42) or IAPP amyloidogenesis has been derived from their target polypeptides.…”

Bicyclic Peptides as Next‐Generation Therapeutics

“…These efforts have resulted in numerous potent, selective monocyclic peptide inhibitors against both extracellular and intracellular proteins including many PPI targets. [2] In general, monocyclic peptides of small ring sizes (<10 amino acids) are relatively resistant to proteases and some have demonstrated oral bioavailability. [3] As the ring size increases, however, monocyclic peptides become progressively more conformationally flexible and susceptible to proteolytic degradation, especially when they consist of predominantly proteinogenic amino acids.…”