Cyclic Peptides as Modulators of Protein-Protein Interactions

Biological processes operate through intricate networks comprised of a myriad of interacting molecules. Protein-protein interactions (PPIs) permeate these networks and are able to transmit and integrate the signalling pathways inside the cells in response to physiological and non-physiological conditions (including cellular pathologies as cancer). To assess the role of such interactions, peptidic compounds have been developed aiming to modulate intracellular PPIs. For instance, structural studies demonstrated in humans and roundworms that the α-helical MAML1 polypeptide binds to a groove formed by the PPI between ICN1 and CLS proteins. The ICN1-CLS-MAML ternary complex plays a key role on NOTCH1 signalling pathway by recruiting the transcription machinery and leading to the transcription of oncogenic NOTCH1 target genes. The group of Dr. James E. Bradner (Harvard Medical School) have designed short α-helical peptides based on a fragment of MAML1 that disrupts the PPI ICN1-CLS, repressing the transcription of NOTCH1 target genes in leukemic cells.

Protein-Protein Interactions
Protein-Protein Interactions

Cyclic peptides form a very exciting group of compounds (and yet, poorly explored) with unique properties. Compared to linear ones, cyclic peptides have higher metabolic stability and higher membrane permeability, making them suitable compounds for therapeutic applications. Cyclosporine for example, one the most medically used cyclic peptide, can easily move across cellular membranes.

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