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Pharmaceuticals
Volume 15
Issue 12
10.3390/ph15121506
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Article

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

by
Kumiko Tsuihiji
1,*,
Eiji Honda
2,
Kanehisa Kojoh
1,
Shizue Katoh
1,
Tomonori Taguri
2,
Atsushi Yoshimori
3 and
Hajime Takashima
2,*
1
Drug Discovery Division, GeneFrontier Corporation, SHARP Kashiwa Building, 4F 273-1 Kashiwa, Kashiwa-shi 277-0005, Chiba, Japan
2
PRISM BioLab Co., Ltd., C21F-4110, 26-1 Muraoka-Higashi 2-Chome, Fujisawa 251-8555, Kanagawa, Japan
3
Chemoinformatics & AI Research Group, Institute for Theoretical Medicine, Inc., BW3M-20B, 26-1 Muraoka-Higashi 2-Chome, Fujisawa 251-0012, Kanagawa, Japan
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2022, 15(12), 1506; https://doi.org/10.3390/ph15121506
Submission received: 4 November 2022 / Revised: 26 November 2022 / Accepted: 29 November 2022 / Published: 2 December 2022
(This article belongs to the Special Issue Small Molecules Targeting Protein-Protein Interactions (PPIs): Current Strategies for the Development of New Drugs)
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Abstract

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® (PUREfrex®RD) to get structure–activity relation (SAR) information. Based on that information, we converted cyclic peptides to small molecules using PepMetics® scaffolds that can mimic the α-helix or β-turn of the peptide. Finally, we succeeded in generating small-molecule compounds with good IC50 (single-digit μM 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.
Keywords: CTLA-4 B7-1 inhibitors; cyclic peptides; molecular docking; PepMetics; peptidomimetics; protein–protein interaction; PURE system; ribosome display; sequence mimic CTLA-4 B7-1 inhibitors; cyclic peptides; molecular docking; PepMetics; peptidomimetics; protein–protein interaction; PURE system; ribosome display; sequence mimic
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MDPI and ACS Style

Tsuihiji, K.; Honda, E.; Kojoh, K.; Katoh, S.; Taguri, T.; Yoshimori, A.; Takashima, H. Rational Strategy for Designing Peptidomimetic Small Molecules Based on Cyclic Peptides Targeting Protein–Protein Interaction between CTLA-4 and B7-1. Pharmaceuticals 2022, 15, 1506. https://doi.org/10.3390/ph15121506

AMA Style

Tsuihiji K, Honda E, Kojoh K, Katoh S, Taguri T, Yoshimori A, Takashima H. Rational Strategy for Designing Peptidomimetic Small Molecules Based on Cyclic Peptides Targeting Protein–Protein Interaction between CTLA-4 and B7-1. Pharmaceuticals. 2022; 15(12):1506. https://doi.org/10.3390/ph15121506

Chicago/Turabian Style

Tsuihiji, Kumiko, Eiji Honda, Kanehisa Kojoh, Shizue Katoh, Tomonori Taguri, Atsushi Yoshimori, and Hajime Takashima. 2022. "Rational Strategy for Designing Peptidomimetic Small Molecules Based on Cyclic Peptides Targeting Protein–Protein Interaction between CTLA-4 and B7-1" Pharmaceuticals 15, no. 12: 1506. https://doi.org/10.3390/ph15121506

APA Style

Tsuihiji, K., Honda, E., Kojoh, K., Katoh, S., Taguri, T., Yoshimori, A., & Takashima, H. (2022). Rational Strategy for Designing Peptidomimetic Small Molecules Based on Cyclic Peptides Targeting Protein–Protein Interaction between CTLA-4 and B7-1. Pharmaceuticals, 15(12), 1506. https://doi.org/10.3390/ph15121506

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