Targeting intracellular protein–protein interactions with cell-permeable cyclic peptides

Abstract

Intracellular protein-protein interactions (PPIs) are challenging targets for conventional drug modalities, because small molecules generally do not bind to their large, flat binding sites with high affinity, whereas monoclonal antibodies cannot cross the cell membrane to reach the targets. Cyclic peptides in the 700–2000 molecular-weight range have the sufficient size and a balanced conformational flexibility/rigidity for binding to flat PPI interfaces with antibody-like affinity and specificity. Several powerful cyclic peptide library technologies were developed over the past decade to rapidly discover potent, specific cyclic peptide ligands against proteins of interest including those involved in PPIs. Methods are also being developed to enhance the membrane permeability of cyclic peptides through both passive diffusion and active transport mechanisms. Integration of the permeability-enhancing elements into cyclic peptide design has led to an increasing number of cell-permeable and biologically active cyclic peptides against intracellular PPIs. In this account, we review the recent developments in the design and synthesis of cell-permeable cyclic peptides.

Intramolecular hydrogen bonding: An opportunity for improved design in medicinal chemistry

“…And secondly, using specific IMHBs to modulate the overall IMHB impact on potency and permeability is the most risky strategy. 41 N-methylation 16 and more recently Lipophilic Prodrug Charge…”

“…However, it was shown that the physicochemical properties (e.g., lipophilicity and charge) and flexibility of cyclic hexapeptides direct their membrane permeation mechanisms. [13][14][15] IMHB, which modulates conformation and thus molecular lipophilicity is, therefore, an accepted key factor impacting on the permeability of cyclic hexapeptides, 5,16 which can provide medicinal chemists with significant help by acting as an additional tool that facilitates their design efforts.…”

Synthetic Cyclic Peptomers as Type III Secretion System Inhibitors

“…These peptomers were not previously screened for any bioactivity and may have a high intrinsic potential to disrupt protein-protein interactions (30), such as those critical for assembly of a large proteinaceous structure such as the T3SS. The compounds were screened for the ability to inhibit NF-B activation during Y. pseudotuberculosis Δyop6 infection of HEK293-GFP cells.…”

Breaking the Fourth Wall: Modulating Quaternary Associations for Protein Regulation and Drug Discovery

“…Given the need to compete against high‐affinity PPIs, some PPI blockers are larger than traditional small‐molecule therapeutics. Such large molecules can have poor cell permeability . This issue was encountered for the small molecule MM401 (Scheme ), which disrupted the interaction between WDR5 (a scaffolding protein involved in histone regulation) and MLL1 (a histone methyl transferase that positively regulates transcription) .…”

“…Such large molecules can have poor cell permeability. [65] This issue was encountered for the small molecule MM401 (Scheme 1), which disrupted the interaction between WDR5 (a scaffolding protein involved in histone regulation) and MLL1 (a histonem ethyl transferase that positively regulates transcription). [66] The WDR5/MLL1 PPI drivesa cutel ymphoblastic leukemia (ALL) with am ixed linear leukemic gene ( Figure 5).…”