Design and syntheses of a bimolecular STING agonist based on the covalent STING antagonist
Ruochen Zang1, Liang Xue2, Meifang Zhang3
1Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Department of Clinical Laboratory, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266100, China.
Abstract:
Cyclic GMP-AMP synthase and stimulator of interferon genes (cGAS-STING) signaling stimulators, an essential innate immunity component, monitor invading pathogen DNA and damaged self-DNA, making them an appealing target for drug development. The natural STING agonist, 2'3'-cGAMP, mounts and stabilizes the STING homodimer to trigger an antiviral or antitumor immune responses. However, cyclic-dinucleotide-based STING agonists show limited clinical effects owing to their short half-lives. To explore whether STING-dimer stabilizers could trigger STING signaling instead of cyclic dinucleotide-based molecules, we analyzed the structural characteristics of STING to design and synthesize a series of compounds based on the covalent STING inhibitor C-170, three of which were 23, 26, and 27, exhibited STING-dependent immune activation, both in vitro and in vivo. Compound 23 could act synergistically with cGAMP and other STING agonists as a promising moderate STING agonist. This indicates that promoting STING dimerization is a promising strategy for designing next-generation STING agonists.
