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Rational design of a potent macrocyclic peptide inhibitor targeting the PD-1/PD-L1 protein-protein interaction.

ABSTRACT: We report optimization by rational design of JMPDP-027, a potent cyclic peptide that interferes with the PD-1/PD-L1 protein-protein interaction. JMPDP-027 shows a potent restoring ability towards T-cells with an EC₅₀ of 5.9 nM that is comparable to that of the anti-PD-1 monoclonal antibody pembrolizumab. In addition, JMPDP-027 shows not only high resistance to enzymatic hydrolysis in human serum but also no observable toxicity and potent in vivo anticancer activity comparable to that of the mouse PD-L1 antibody in a colon carcinoma (CT26) model. Cyclic peptide antagonists of this sort may provide novel drug candidates for cancer immunotherapy.

SUBMITTER: Miao Q

PROVIDER: S-EPMC9036676 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Rational design of a potent macrocyclic peptide inhibitor targeting the PD-1/PD-L1 protein-protein interaction.

Miao Qi Q Zhang Wanheng W Zhang Kuojun K Li He H Zhu Jidong J Jiang Sheng S

RSC advances 20210701 38

We report optimization by rational design of JMPDP-027, a potent cyclic peptide that interferes with the PD-1/PD-L1 protein-protein interaction. JMPDP-027 shows a potent restoring ability towards T-cells with an EC<sub>50</sub> of 5.9 nM that is comparable to that of the anti-PD-1 monoclonal antibody pembrolizumab. In addition, JMPDP-027 shows not only high resistance to enzymatic hydrolysis in human serum but also no observable toxicity and potent <i>in vivo</i> anticancer activity comparable t ...[more]

PMID: 35479790

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