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The Stone Guest: How Does pH Affect Binding Properties of PD‐1/PD‐L1 Inhibitors?
ChemMedChem ( IF 3.6 ) Pub Date : 2020-10-21 , DOI: 10.1002/cmdc.202000760 Alessandra Riccio 1 , Alice Coletti 2 , Daniela Dolciami 1 , Andrea Mammoli 1 , Bruno Cerra 1 , Sonia Moretti 2 , Antimo Gioiello 1 , Simone Ferlin 3 , Efisio Puxeddu 2 , Antonio Macchiarulo 1
ChemMedChem ( IF 3.6 ) Pub Date : 2020-10-21 , DOI: 10.1002/cmdc.202000760 Alessandra Riccio 1 , Alice Coletti 2 , Daniela Dolciami 1 , Andrea Mammoli 1 , Bruno Cerra 1 , Sonia Moretti 2 , Antimo Gioiello 1 , Simone Ferlin 3 , Efisio Puxeddu 2 , Antonio Macchiarulo 1
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The interaction between programmed cell death‐1 (PD‐1) and its ligand PD−L1 activates a coinhibitory signal that blocks T‐cell activation, promoting the immune escape process in the tumor microenvironment. Development of monoclonal antibodies targeting and inhibiting PD‐1/PD−L1 interaction as anticancer immunotherapies has proved successful in multiple clinical settings and for various types of cancer. Notwithstanding, limitations exist with the use of these biologics, including drug resistance and narrow therapeutic response rate in a majority of patients, that demand for the design of more efficacious small molecule‐based immunotherapies. Alteration of pH in the tumor microenvironment is a key factor that is involved in promoting drug resistance, tumor survival and progression. In this study, we have investigated the effect of pH shifts on binding properties of distinct classes of PD−L1 inhibitors, including macrocyclic peptide and small molecules. Results expand structure‐activity relationships of PD−L1 inhibitors, providing insights into structural features and physicochemical properties that are useful for the design of ligands that may escape a drug resistance mechanism associated to variable pH conditions of tumor microenvironment.
中文翻译：
The Stone Guest：pH 如何影响 PD-1/PD-L1 抑制剂的结合特性？
程序性细胞死亡-1 (PD-1) 与其配体 PD-L1 之间的相互作用激活了一种抑制 T 细胞活化的共抑制信号，促进了肿瘤微环境中的免疫逃逸过程。开发靶向和抑制 PD-1/PD-L1 相互作用的单克隆抗体作为抗癌免疫疗法已在多种临床环境和各种类型的癌症中取得成功。尽管如此，这些生物制剂的使用存在局限性，包括大多数患者的耐药性和狭窄的治疗反应率，这需要设计更有效的基于小分子的免疫疗法。肿瘤微环境中 pH 值的改变是参与促进耐药性、肿瘤存活和进展的关键因素。在这项研究中，我们研究了 pH 变化对不同类别 PD-L1 抑制剂（包括大环肽和小分子）结合特性的影响。结果扩展了 PD-L1 抑制剂的构效关系，提供了对结构特征和理化特性的见解，这些特性和理化特性有助于设计配体，这些配体可能会逃避与肿瘤微环境可变 pH 条件相关的耐药机制。
更新日期：2020-10-21
中文翻译：
The Stone Guest：pH 如何影响 PD-1/PD-L1 抑制剂的结合特性？
程序性细胞死亡-1 (PD-1) 与其配体 PD-L1 之间的相互作用激活了一种抑制 T 细胞活化的共抑制信号，促进了肿瘤微环境中的免疫逃逸过程。开发靶向和抑制 PD-1/PD-L1 相互作用的单克隆抗体作为抗癌免疫疗法已在多种临床环境和各种类型的癌症中取得成功。尽管如此，这些生物制剂的使用存在局限性，包括大多数患者的耐药性和狭窄的治疗反应率，这需要设计更有效的基于小分子的免疫疗法。肿瘤微环境中 pH 值的改变是参与促进耐药性、肿瘤存活和进展的关键因素。在这项研究中，我们研究了 pH 变化对不同类别 PD-L1 抑制剂（包括大环肽和小分子）结合特性的影响。结果扩展了 PD-L1 抑制剂的构效关系，提供了对结构特征和理化特性的见解，这些特性和理化特性有助于设计配体，这些配体可能会逃避与肿瘤微环境可变 pH 条件相关的耐药机制。
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