Identification of Ziyuglycoside II from a Natural Products Library as a STING Agonist.

Abstract

Given the emerging pivotal roles of stimulator of interferon genes (STING) in host pathogen defense and immune-oncology, STING is regarded as a promising target for drug development. Cyclic dinucleotides (CDNs) are the first-generation STING agonists. However, their poor metabolic stability and membrane permeability limits their therapeutic application. In contrast, small-molecule STING agonists show superior properties such as molecular weight, polar character, and delivery diversity. The quest for a potent small-molecular agonist of human STING remains ongoing. In our study, through an IRF/IFN pathway-targeted cell-based screen of a natural products library, we identified a small-molecular STING agonist, Ziyuglycoside II, termed ST12, with potent stimulation of the IRF/IFN and NF-κB pathways. Furthermore, its binding to the C-terminal domain of human STING, detected by bio-layer interferometry, indicates that ST12 is a human STING agonist. Further Tanimoto similarity analysis with existing small-molecule STING agonists indicates that ST12 is a lead compound with a novel core structure for the further optimization.

• Authors: Xiangling Cui, Yongli Xie, Min Zhang, Jieke Gao, Xujun Zhou, Jiwei Ding, Shan Cen, Jinming Zhou
• Journal: ChemMedChem (ChemMedChem) Vol. 17 Issue 11 Pg. e202100719 (06 03 2022) ISSN: 1860-7187 [Electronic] Germany
• PMID: 35293138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 Wiley-VCH GmbH.

Chemical References

• Biological Products
• Membrane Proteins
• Saponins
• ziyuglycoside II

Topics

• Biological Products (pharmacology)
• Humans
• Membrane Proteins (metabolism)
• Saponins