Design and Biophysical Characterization of Second-Generation Cyclic Peptide LAG-3 Inhibitors for Cancer Immunotherapy

Laura Calvo-Barreiro, Longfei Zhang, Yaser Ali, Ashfaq Ur Rehman, Moustafa Gabr
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Abstract

Lymphocyte activation gene 3 (LAG-3) is an inhibitory immune checkpoint crucial for suppressing the immune response against cancer. Blocking LAG-3 interactions enables T cells to recover their cytotoxic capabilities and diminishes the immunosuppressive effects of regulatory T cells. A cyclic peptide (Cys-Val-Pro-Met-Thr-Tyr-Arg-Ala-Cys, disulfide bridge: 1-9) was recently reported as a LAG-3 inhibitor. Based on this peptide, we designed 19 derivatives by substituting tyrosine residue to maximize LAG-3 inhibition. Screening via TR-FRET assay identified 8 outperforming derivatives, with cyclic peptides 12 [Tyr6(L-3-CN-Phe)], 13 [Tyr6(L-4-NH2-Phe)], and 17 [Tyr6(L-3,5-DiF-Phe)] as top candidates. Cyclic peptide 12 exhibited the highest inhibition (IC50 = 4.45 ± 1.36 μM). MST analysis showed cyclic peptides 12 and 13 bound LAG-3 with KD values of 2.66 ± 2.06 μM and 1.81 ± 1.42 μM, respectively, surpassing the original peptide (9.94 ± 4.13 μM). Docking simulations indicated enhanced binding for cyclic peptide 12, with a docking score of -7.236 kcal/mol compared to -5.236 kcal/mol for the original peptide.
用于癌症免疫疗法的第二代环肽 LAG-3 抑制剂的设计与生物物理特性分析
淋巴细胞活化基因 3(LAG-3)是一种抑制性免疫检查点,对抑制抗癌免疫反应至关重要。阻断 LAG-3 的相互作用可使 T 细胞恢复其细胞毒性能力,并削弱调节性 T 细胞的免疫抑制作用。最近有报道称一种环肽(Cys-Val-Pro-Met-Thr-Tyr-Arg-Ala-Cys,二硫桥:1-9)可作为 LAG-3 抑制剂。在该肽的基础上,我们通过取代酪氨酸残基设计了 19 种衍生物,以最大限度地抑制 LAG-3。通过 TR-FRET 分析筛选出 8 种性能更优越的衍生物,其中环肽 12 [Tyr6(L-3-CN-Phe)]、13 [Tyr6(L-4-NH2-Phe)] 和 17 [Tyr6(L-3,5-DiF-Phe)] 为最佳候选。环肽 12 的抑制率最高(IC50 = 4.45 ± 1.36 μM)。MST 分析表明,环肽 12 和 13 与 LAG-3 结合的 KD 值分别为 2.66 ± 2.06 μM 和 1.81 ± 1.42 μM,超过了原始肽(9.94 ± 4.13 μM)。对接模拟显示环肽 12 的结合力增强,对接得分为 -7.236 kcal/mol,而原始肽的对接得分为 -5.236 kcal/mol。
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