Structure-Based Rational Design of Constrained Peptides as TIM-3 Inhibitors

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-05-28 DOI:10.1021/acsmedchemlett.3c00567

Somaya A. Abdel-Rahman, Victor Ovchinnikov and Moustafa T. Gabr*,

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Abstract

Blocking the immunosuppressive function of T-cell immunoglobulin mucin-3 (TIM-3) is an established therapeutic strategy to maximize the efficacy of immune checkpoint inhibitors for cancer immunotherapy. Currently, effective inhibition of TIM-3 interactions relies on monoclonal antibodies (mAbs), which come with drawbacks such as immunogenicity risk, limited tumor penetration, and high manufacturing costs. Guided by the X-ray cocrystal structures of TIM-3 with mAbs, we report an in silico structure-based rational design of constrained peptides as potent TIM-3 inhibitors. The top cyclic peptide from our study (P2) binds TIM-3 with a K_D value of 166.3 ± 12.1 nM as determined by surface plasmon resonance (SPR) screening. Remarkably, P2 efficiently inhibits key TIM-3 interactions with natural TIM-3 ligands at submicromolar concentrations in a panel of cell-free and cell-based assays. The capacity of P2 to reverse immunosuppression in T-cell/cancer cell cocultures, coupled with favorable in vitro pharmacokinetic properties, highlights the potential of P2 for further evaluation in preclinical models of immuno-oncology.

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基于结构合理设计作为 TIM-3 抑制剂的受限多肽

阻断 T 细胞免疫球蛋白粘蛋白-3（TIM-3）的免疫抑制功能是一种成熟的治疗策略，可最大限度地提高免疫检查点抑制剂在癌症免疫疗法中的疗效。目前，有效抑制 TIM-3 相互作用依赖于单克隆抗体（mAbs），但这种抗体存在免疫原性风险、肿瘤穿透力有限和制造成本高等缺点。在 TIM-3 与 mAbs 的 X 射线共晶体结构的指导下，我们报告了一种基于结构的受限肽作为强效 TIM-3 抑制剂的硅学理性设计。通过表面等离子体共振（SPR）筛选，我们研究中的顶级环肽（P2）与 TIM-3 的结合 KD 值为 166.3 ± 12.1 nM。值得注意的是，在一系列无细胞和基于细胞的试验中，P2 在亚摩尔浓度下就能有效抑制 TIM-3 与天然 TIM-3 配体的关键相互作用。P2 在 T 细胞/癌细胞共培养物中逆转免疫抑制的能力，加上良好的体外药代动力学特性，凸显了 P2 在免疫肿瘤学临床前模型中进一步评估的潜力。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.