2. Academic Validation
  3. Design and syntheses of a bimolecular STING agonist based on the covalent STING antagonist

Design and syntheses of a bimolecular STING agonist based on the covalent STING antagonist

  • Eur J Med Chem. 2023 Feb 4;250:115184. doi: 10.1016/j.ejmech.2023.115184.
Ruochen Zang 1,  Liang Xue 2,  Meifang Zhang 3,  Xiaoyue Peng 3,  Xionghao Li 3,  Kaixin Du 3,  Chuanqin Shi 4,  Yuqian Liu 3,  Yuxi Lin 5,  Wenwei Han 6,  Rilei Yu 3,  Qian Wang 7,  Jinbo Yang 8,  Xin Wang 9,  Tao Jiang 10
Affiliations

Affiliations

  • 1 Key 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.
  • 2 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts and Innovation Center for Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266003, China.
  • 3 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
  • 4 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Center of Translational Medicine, ZiBo Central Hospital, Zibo, 255036, China.
  • 5 Institute of Cancer Biology and Drug Screening, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China.
  • 6 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, 266071, China.
  • 7 Department of Clinical Laboratory, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266100, China; Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, 250012, China.
  • 8 Marine Drug Screening and Evaluation Platform, Qingdao National Laboratory for Marine Science and Technology, Ocean University of China, Qingdao, 266071, China.
  • 9 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Marine Drug Screening and Evaluation Platform, Qingdao National Laboratory for Marine Science and Technology, Ocean University of China, Qingdao, 266071, China. Electronic address: wx8399@ouc.edu.cn.
  • 10 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts and Innovation Center for Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266003, China. Electronic address: jiangtao@ouc.edu.cn.
PMID: 36758305 DOI: 10.1016/j.ejmech.2023.115184
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.

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