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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Peptide-based and small synthetic molecule inhibitors on PD-1/PD-L1 pathway: A new choice for immunotherapy?
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Peptide-based and small synthetic molecule inhibitors on PD-1/PD-L1 pathway: A new choice for immunotherapy?

机译：PD-1 / PD-L1途径基于肽和小合成分子抑制剂：免疫疗法的新选择？

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摘要

Blockade the interaction of the programmed cell death protein 1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1) can prevent immune evasion of tumor cells and significantly prolong the survival of cancer patients. Currently marketed drugs targeting PD-1/PD-L1 pathway are all monoclonal antibodies (mAbs) that have achieved great success in clinical trials. With the constantly emerging problems of antibody drugs, small molecule inhibitors have attracted the attention of pharmaceutical chemists due to their controllable pharmacological and pharmacokinetic properties, which make them potential alternatives or supplements to mAbs to regulate PD-1/PD-L1 pathway. However, the insufficient target structure information hinders the development of small molecule inhibitors. Since the publication of human-PD-1/human-PD-L1 (hPD-1/hPD-L1) crystal structure, more and more cocrystal structures of mAbs, cyclopeptides and small molecules with PD-1 and PD-L1 have been resolved. These complexes provide a valuable starting point for the rational design of peptide-based and small synthetic molecule inhibitors. Here we reviewed the non-antibody inhibitors that have been published so far and analyzed their structure-activity relationships (SAR). We also summarized the cocrystal structures with hot spots identified, with the aim to provide reference for future drug discovery.
机译：阻止编程的细胞死亡蛋白1（PD-1）及其配体的相互作用，编程的死亡 - 配体1（PD-L1）可以防止肿瘤细胞的免疫逃避并显着延长癌症患者的存活。目前销售的药物靶向PD-1 / PD-L1途径是所有单克隆抗体（MAB），在临床试验中取得了巨大的成功。随着抗体药物的不断新出现的问题，由于其可控药理学和药代动力学性质，小分子抑制剂引起了药物化学家的注意力，这使得它们使其成为MAB的潜在替代品或补充剂来调节PD-1 / PD-L1途径。然而，目标结构信息不足阻碍了小分子抑制剂的发展。由于已经解决了人PD-1 /人PD-L1（HPD-1 / HPD-L1）晶体结构的越来越多的MAb，环庚酯和具有PD-1和PD-L1的小分子的越来越多的晶体结构。这些配合物为肽的基础和小合成分子抑制剂的合理设计提供了有价值的起点。在这里，我们审查了到目前为止公布的非抗体抑制剂，并分析了它们的结构 - 活动关系（SAR）。我们还综述了具有热点的Cocrystal结构，目的是为未来的药物发现提供参考。

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