Calvo-Barreiro Laura, Secor Maxim, Damjanovic Jovan, Abdel-Rahman Somaya A, Lin Yu-Shan, Gabr Moustafa
Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, New York, USA.
Department of Chemistry, Tufts University, Medford, Massachusetts, USA.
Chem Biol Drug Des. 2025 May;105(5):e70117. doi: 10.1111/cbdd.70117.
The interaction between the inducible T-cell costimulatory molecule (ICOS) and its ligand (ICOS-L) is a critical pathway in T-cell activation and immune regulation. We computationally designed a bicyclic peptide (CP5) that inhibits the ICOS/ICOS-L protein-protein interaction (PPI). Using the structural insights derived from the ICOS/ICOS-L co-crystal structure (PDB: 6X4G) and bias-exchange metadynamics simulations (BE-META), we first designed monocyclic peptide candidates containing the β-strand (residues 51-55 YVYWQ) of ICOS-L that interact with ICOS. Using Rosetta's flex ddG calculations and further disulfide-bond restraint, we arrived at CP5 (cyclo-RVY[CQPGWC]WVLpG) as a potential ICOS/ICOS-L inhibitor. Using dynamic light scattering (DLS), we examined the interaction between CP5 and ICOS. Importantly, we validated the ICOS/ICOS-L inhibitory activity of CP5 using both TR-FRET assay and ELISA. Notably, CP5 demonstrated satisfactory in vitro pharmacokinetic properties, such as metabolic stability and lipophilicity, positioning it as a promising candidate for further drug development. Our findings provide a foundation for future drug discovery efforts aiming to develop cyclic peptides that specifically target the ICOS/ICOS-L interaction.
诱导性T细胞共刺激分子（ICOS）与其配体（ICOS-L）之间的相互作用是T细胞活化和免疫调节的关键途径。我们通过计算设计了一种双环肽（CP5），它可抑制ICOS/ICOS-L蛋白-蛋白相互作用（PPI）。利用从ICOS/ICOS-L共晶体结构（PDB：6X4G）和偏差交换元动力学模拟（BE-META）中获得的结构见解，我们首先设计了包含与ICOS相互作用的ICOS-L的β链（残基51-55 YVYWQ）的单环肽候选物。通过Rosetta的flex ddG计算和进一步的二硫键限制，我们得到了CP5（环-RVY[CQPGWC]WVLpG）作为一种潜在的ICOS/ICOS-L抑制剂。利用动态光散射（DLS），我们研究了CP5与ICOS之间的相互作用。重要的是，我们使用时间分辨荧光能量共振转移（TR-FRET）测定法和酶联免疫吸附测定（ELISA）验证了CP5对ICOS/ICOS-L的抑制活性。值得注意的是，CP5表现出令人满意的体外药代动力学性质，如代谢稳定性和亲脂性，使其成为进一步药物开发的有前景的候选物。我们的研究结果为未来旨在开发特异性靶向ICOS/ICOS-L相互作用的环肽的药物发现工作奠定了基础。
