Guangdong Provincial Key Laboratory of New Drug Screening and Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Guangdong Provincial Key Laboratory of New Drug Screening and Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Eur J Med Chem. 2019 May 1;169:42-52. doi: 10.1016/j.ejmech.2019.02.067. Epub 2019 Mar 1.
Previous high throughput virtual screening of 10 million-compound and following cell based validation led to the discovery of a novel, nonlipopeptide-like chemotype ZINC 6662436, as toll-like receptor 2 (TLR2) agonists. In this report, compounds belonging to four areas of structural modification of ZINC6662436 were evaluated for biological activity using human HEK-Blue TLR2 reporter cells, and human THP-1 monocytic cells, yield SMU-C13 as an optimized, direct and high potent (EC = 160 nM) agonist of human TLR2. Moreover, preliminary mechanism studies indicated that SMU-C13 through activates TLR1 and TLR2 then stimulates the NF-κB activation to trigger the downstream cytokines, such as TNF-α and secreted alkaline phosphatase (SEAP).
先前对 1000 万种化合物进行高通量虚拟筛选，并进行基于细胞的验证，导致发现了一种新型的非脂肽样化学型 ZINC 6662436，作为 Toll 样受体 2（TLR2）激动剂。在本报告中，使用人 HEK-Blue TLR2 报告细胞和人 THP-1 单核细胞评估了属于 ZINC6662436 四个结构修饰区域的化合物的生物学活性，得到了优化的、直接的和高效（EC=160nM）人 TLR2 激动剂 SMU-C13。此外，初步的机制研究表明，SMU-C13 通过激活 TLR1 和 TLR2，然后刺激 NF-κB 激活，引发下游细胞因子，如 TNF-α 和碱性磷酸酶（SEAP）的分泌。
