Design of cyclic peptides as novel inhibitors of ICOS/ICOSL interaction

Somaya A. Abdel‐Rahman, Brianda L. Santini, Laura Calvo-Barreiro, Martin Zacharias, Moustafa Gabr

Research output: Contribution to journalArticlepeer-review

Abstract

Compared to small molecules and antibodies, cyclic peptides exhibit unique biochemical and therapeutic attributes in the realm of pharmaceutical applications. The interaction between the inducible costimulator (ICOS) and its ligand (ICOSL) plays a key role in T-cell differentiation and activation. ICOS/ICOSL inhibition results in a reduction in the promotion of immunosuppressive regulatory T cells (Tregs) in both hematologic malignancies and solid tumors. Herein, we implement the computational cPEPmatch approach to design the first examples of cyclic peptides that inhibit ICOS/ICOSL interaction. The top cyclic peptide from our approach possessed an IC50 value of 1.87 ± 0.15 μM as an ICOS/ICOSL inhibitor and exhibited excellent in vitro pharmacokinetic properties as a drug candidate. Our work will lay the groundwork for future endeavors in cancer drug discovery, with the goal of developing cyclic peptides that target the ICOS/ICOSL interaction.

Original languageEnglish
Article number129599
JournalBioorganic and Medicinal Chemistry Letters
Volume99
DOIs
StatePublished - 1 Feb 2024
Externally publishedYes

Keywords

  • Computational chemistry
  • Cyclic peptides
  • ICOS
  • Immune checkpoints
  • Immunomodulators

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