The Stone Guest: How Does pH Affect Binding Properties of PD-1/PD-L1 Inhibitors? |
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Authors: | Dr Alessandra Riccio Dr Alice Coletti Dr Daniela Dolciami Dr Andrea Mammoli Dr Bruno Cerra Dr Sonia Moretti Prof Antimo Gioiello Dr Simone Ferlin Prof Efisio Puxeddu Prof Antonio Macchiarulo |
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Affiliation: | 1. Department of Pharmaceutical Sciences, University of Perugia, via del liceo n.1, 06123 Perugia, Italy;2. Department of Medicine, University of Perugia, via Gambuli, 1, 06132 Perugia, Italy;3. Sterling S.p.A., Via della Carboneria, 30, 06073 Corciano, Perugia, Italy |
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Abstract: | 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. |
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Keywords: | Immunotherapy Checkpoint inhibitors Thermophoresis Molecular dynamics Cancer |
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