Department of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado Boulder , Boulder, Colorado 80309, United States.
J Med Chem. 2017 Jun 22;60(12):5029-5044. doi: 10.1021/acs.jmedchem.7b00419. Epub 2017 Jun 6.
Therapies based on activation of multiple Toll-like receptors (TLRs) may offer superior therapeutic profiles than that of single TLR activation. To discover new small molecules that could activate multiple TLRs, we performed a cell-based high-throughput screening of a small-molecule library based on TLR3-mediated NF-κB activation. Subsequent structural optimization and counterscreening of other TLRs produced the first small molecule 17e (CU-CPT17e) capable of simultaneously activating TLRs 3, 8, and 9. Biochemical studies demonstrated that 17e could induce a strong immune response via the production of various cytokines in human monocytic THP-1 cells. Furthermore, 17e inhibited the proliferation of HeLa cancer cells by triggering apoptosis and arresting the cell cycle at the S phase. These results showcase potential therapeutic applications of 17e in both vaccine adjuvants and anticancer therapies based on multi-TLR activation.
基于多种 Toll 样受体（TLR）激活的疗法可能比单一 TLR 激活具有更优越的治疗效果。为了发现能够激活多种 TLR 的新小分子，我们基于 TLR3 介导的 NF-κB 激活，对小分子文库进行了基于细胞的高通量筛选。随后对其他 TLR 进行结构优化和反筛选，得到了第一个能够同时激活 TLR3、8 和 9 的小分子 17e（CU-CPT17e）。生化研究表明，17e 可以通过在人单核细胞 THP-1 细胞中产生各种细胞因子来诱导强烈的免疫反应。此外，17e 通过触发细胞凋亡并将细胞周期阻滞在 S 期来抑制 HeLa 癌细胞的增殖。这些结果表明 17e 在基于多 TLR 激活的疫苗佐剂和抗癌疗法方面具有潜在的治疗应用。
