2. Academic Validation
  3. Marine diterpenoid targets STING palmitoylation in mammalian cells

Marine diterpenoid targets STING palmitoylation in mammalian cells

  • Commun Chem. 2023 Jul 18;6(1):153. doi: 10.1038/s42004-023-00956-9.
Wan-Chi Hsiao # 1 2,  Guang-Hao Niu # 3,  Chen-Fu Lo 3,  Jing-Ya Wang 3,  Ya-Hui Chi 3,  Wei-Cheng Huang 3,  Chun-Wei Tung 3,  Ping-Jyun Sung 4 5 6 7,  Lun Kelvin Tsou 8,  Mingzi M Zhang 9
Affiliations

Affiliations

  • 1 Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, 35053, Taiwan.
  • 2 Institute of Biotechnology, National Tsing Hua University, Hsinchu, 30013, Taiwan.
  • 3 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, 35053, Taiwan.
  • 4 Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, 804201, Taiwan. pjsung@nmmba.gov.tw.
  • 5 National Museum of Marine Biology and Aquarium, Pingtung, 944401, Taiwan. pjsung@nmmba.gov.tw.
  • 6 Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, 404394, Taiwan. pjsung@nmmba.gov.tw.
  • 7 Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, 807378, Taiwan. pjsung@nmmba.gov.tw.
  • 8 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, 35053, Taiwan. kelvintsou@nhri.edu.tw.
  • 9 Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, 35053, Taiwan. zhangmz@nhri.edu.tw.
  • # Contributed equally.
PMID: 37463995 DOI: 10.1038/s42004-023-00956-9
Abstract

Natural Products are important sources of therapeutic agents and useful drug discovery tools. The fused macrocycles and multiple stereocenters of briarane-type Diterpenoids pose a major challenge to total synthesis and efforts to characterize their biological activities. Harnessing a scalable source of excavatolide B (excB) from cultured soft coral Briareum stechei, we generated analogs by late-stage diversification and performed structure-activity analysis, which was critical for the development of functional excB probes. We further used these probes in a chemoproteomic strategy to identify Stimulator of Interferon Genes (STING) as a direct target of excB in mammalian cells. We showed that the epoxylactone warhead of excB is required to covalently engage STING at its membrane-proximal Cys91, inhibiting STING palmitoylation and signaling. This study reveals a possible mechanism-of-action of excB, and expands the repertoire of covalent STING inhibitors.

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