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Rational Strategy for Designing Peptidomimetic Small Molecules Based on Cyclic Peptides Targeting Protein-Protein

Kumiko Tsuihiji1, Eiji Honda2, Kanehisa Kojoh1

  • 1Drug Discovery Division, GeneFrontier Corporation, SHARP Kashiwa Building, 4F 273-1 Kashiwa, Kashiwa-shi 277-0005, Chiba, Japan.

Pharmaceuticals (Basel, Switzerland)
|December 23, 2022
PubMed
Summary

Researchers developed a two-step strategy to design small-molecule drugs targeting protein-protein interactions (PPIs). This method successfully generated compounds against CTLA-4, offering a promising alternative to antibody drugs.

Keywords:
CTLA-4 B7-1 inhibitorsPURE systemPepMeticscyclic peptidesmolecular dockingpeptidomimeticsprotein–protein interactionribosome displaysequence mimic

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Area of Science:

  • Pharmaceutical Chemistry
  • Drug Discovery
  • Molecular Biology

Background:

  • Targeting protein-protein interactions (PPIs) is crucial for developing new pharmaceutical treatments.
  • Cyclic peptides show promise for PPI targeting but face challenges with oral availability and cell permeability.
  • Small-molecule drugs offer benefits but their screening for PPIs is time-consuming and requires structural analysis.

Purpose of the Study:

  • To investigate a rational two-step strategy for designing small-molecule compounds that target PPIs.
  • To overcome the limitations of cyclic peptides in drug development.
  • To develop an efficient method for PPI-targeting small-molecule discovery without requiring target structural information.

Main Methods:

  • Utilized ribosomal display with PUREfrex® (PUREfrex®RD) to identify inhibitory cyclic peptides against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
  • Obtained structure-activity relation (SAR) data from the identified cyclic peptides.
  • Employed PepMetics® scaffolds to convert cyclic peptides into small molecules mimicking peptide secondary structures (α-helix or β-turn).

Main Results:

  • Successfully generated small-molecule compounds with inhibitory activity against CTLA-4.
  • Achieved IC50 values in the single-digit micromolar range for the designed small molecules.
  • Demonstrated the feasibility of the two-step strategy for PPI-targeting small-molecule design.

Conclusions:

  • The developed two-step strategy provides a valuable approach for designing small-molecule drugs targeting PPIs.
  • This method enables efficient drug discovery without the need for X-ray crystal structures or other detailed target information.
  • The strategy holds potential for advancing the development of novel therapeutics for various diseases involving PPIs.