UC San Diego Moores Cancer Center, University of California San Diego, La Jolla, California 92093, United States.
Department of Medicine, University of California San Diego, La Jolla, California 92093, United States.
J Med Chem. 2024 Aug 22;67(16):13703-13722. doi: 10.1021/acs.jmedchem.4c00491. Epub 2024 Aug 8.
Extracellular vesicles (EVs) can transfer antigens and immunomodulatory molecules, and such EVs released by antigen-presenting cells equipped with immunostimulatory functions have been utilized for vaccine formulations. A prior high-throughput screening campaign led to the identification of compound (), which enhanced EV release and increased intracellular Ca influx. Here, we performed systematic structure-activity relationship (SAR) studies to investigate the scaffold for its potency as a vaccine adjuvant. Synthesized compounds were analyzed in vitro for CD63 reporter activity (a marker for EV biogenesis) in human THP-1 cells, induction of Ca influx, IL-12 production, and cell viability in murine bone-marrow-derived dendritic cells. The SAR studies indicated that the ester functional group was requisite, and the sulfur atom of the benzothiadiazole ring replaced with a higher selenium atom () or a bioisosteric ethenyl group () retained potency. Proof-of-concept vaccination studies validated the potency of the selected compounds as novel vaccine adjuvants.
细胞外囊泡（EVs）可以传递抗原和免疫调节分子，而具有免疫刺激功能的抗原呈递细胞释放的这种 EVs 已被用于疫苗制剂。之前的高通量筛选活动导致了化合物 () 的鉴定，该化合物增强了 EV 的释放并增加了细胞内 Ca2+流入。在这里，我们进行了系统的构效关系（SAR）研究，以研究其作为疫苗佐剂的效力的支架。合成的化合物在体外进行了分析，以评估其在人 THP-1 细胞中 CD63 报告基因活性（EV 发生的标志物）、Ca2+流入诱导、IL-12 产生和小鼠骨髓来源树突状细胞活力方面的活性。SAR 研究表明，酯官能团是必需的，苯并噻二唑环的硫原子被更高的硒原子（）或生物等排乙烯基取代（）保留了效力。概念验证疫苗接种研究验证了所选化合物作为新型疫苗佐剂的效力。
