Design and Discovery of Natural Cyclopeptide Skeleton Based Programmed Death Ligand 1 Inhibitor as Immune Modulator for Cancer Therapy
- 26 August 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (19), 11286-11301
- https://doi.org/10.1021/acs.jmedchem.0c01262
Abstract
Blockade of immune checkpoint PD-1/PD-L1 facilitate the rescue of immune escapes of tumor cells. Though various of monoclonal antibodies have been approved for clinical therapy, the development of small molecular inhibitors lags behind antibodies partially owing to the challenging of protein-protein interaction (PPI) blocker design. In this work, we adopted the skeleton of natural cyclopeptidic antibiotics Gramicidin S as the start point for PD-1/PD-L1 inhibitor exploring, and discovered a series of novel cyclopeptides that could interfere the PPI of PD-1/PD-L1 based on several rounds of structural design and optimization. The representative active cyclopeptide 66 can bind two PD-L1 and efficiently block the PD-1/PD-L1 interaction, recruit the immune cells to the tumor cells, enhance their killing against tumor cells by promoting the release of granzyme B and perforin, and display significant CD8+ T cell-dependent tumor suppression activity in vivo.Keywords
Funding Information
- Guangdong Science and Technology Department (2019A050510019)
- Guangzhou Science and Technology Program key projects (201804010233)
- National Natural Science Foundation of China (21672266, 31701114, 81703370, 81973174)
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