Rational Strategy for Designing Peptidomimetic Small Molecules Based on Cyclic Peptides Targeting Protein-Protein Interaction between CTLA-4 and B7-1

Currently, various pharmaceutical modalities are being developed rapidly. Targeting protein-protein interactions (PPIs) is an important objective in such development. Cyclic peptides, because they have good specificity and activity, have been attracting much attention as an alternative to antibody drugs. However, cyclic peptides involve some difficulties, such as oral availability and cell permeability. Therefore, while small-molecule drugs still present many benefits, the screening of functional small-molecule compounds targeting PPIs requires a great deal of time and effort, including structural analysis of targets and hits. In this study, we investigated a rational two-step strategy to design small-molecule compounds targeting PPIs. First, we obtained inhibitory cyclic peptides that bind to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) by ribosomal display using PUREfrex(R) (PUREfrex(R)RD) to get structure-activity relation (SAR) information. Based on that information, we converted cyclic peptides to small molecules using PepMetics(R) scaffolds that can mimic the alpha-helix or beta-turn of the peptide. Finally, we succeeded in generating small-molecule compounds with good IC50 (single-digit mu M values) against CTLA-4. This strategy is expected to be a useful approach for small-molecule design targeting PPIs, even without having structural information such as that associated with X-ray crystal structures.

Automated summary

Currently, there is a rapid development of various pharmaceutical modalities, with a focus on targeting protein-protein interactions (PPIs). Cyclic peptides have gained attention as potential alternatives to antibody drugs due to their specificity and activity. However, they also present challenges such as oral availability and cell permeability. To overcome these difficulties, this study proposes a rational two-step strategy to design small-molecule compounds targeting PPIs. The strategy involves obtaining inhibitory cyclic peptides and converting them into small molecules using PepMetics(R) scaffolds. The researchers successfully generated small-molecule compounds with good inhibitory activity against CTLA-4. This approach is expected to be a useful method for designing small molecules targeting PPIs, even without structural information.