The Development of a Highly Potent and Selective Human Toll-like Receptor 2 Agonist: Synthesis and Biological Evaluation of CaLGL-1 and Its Derivatives

文献类型： 外文期刊

第一作者： Jia, Hongbin

作者： Jia, Hongbin;Luo, Zhikuan;Jing, Ruijun;Yao, Bowen;Lv, Tinghong;Wang, Xiaolei;Jia, Hongbin;Luo, Zhikuan;Jing, Ruijun;Yao, Bowen;Lv, Tinghong;Wang, Xiaolei;Luo, Zhikuan;Zheng, Haixue;Wang, Xiaolei;Zheng, Haixue

作者机构：

期刊名称：JOURNAL OF MEDICINAL CHEMISTRY （ 影响因子：6.8； 五年影响因子：7.1 ）

ISSN： 0022-2623

年卷期： 2024 年 67 卷 15 期

页码：

收录情况： SCI

摘要： Toll-like receptor 2 (TLR2) plays a crucial role in detecting microbial pathogen-associated molecular patterns, offering potential applications as an adjuvant for vaccines and antitumor therapies. Here, we present the gram-scale synthesis of CaLGL-1 and its derivatives, natural products known for activating mouse TLR2 (EC50 = 3.2 mu M). This synthesis involves a streamlined six-step reaction sequence utilizing oxidant-promoted acetalization, effectively preserving the acid-sensitive glycosidic bond for maintaining the compounds' functional integrity. Our structure-activity relationship studies identified R-7d as a potent human TLR2 activator. It demonstrated subnanomolar activity (EC50 = 116 pM) in human THP-1 cells, comparable to that of diprovocim (EC50 = 110 pM). Experiments revealed that R-7d enhances NF-kB promoter activation through TLR2/TLR1 heterodimers rather than TLR2/TLR6. The discovery of R-7d as a robust human TLR2 agonist opens up new possibilities for combination therapies.

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