Yang Yu, Zhu Jingyu, Hassink Matthew, Jenkins Lisa M Miller, Wan Yanmin, Appella Daniel H, Xu Jianqing, Appella Ettore, Zhang Xiaoyan
Scientific Research Center, Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology, Fudan University, Shanghai 201508, China.
Synthetic Bioactive Molecules Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20814, USA.
Emerg Microbes Infect. 2017 Jun 7;6(6):e40. doi: 10.1038/emi.2017.26.
The strategy of simultaneously attacking multiple targets is worthy of exploration in the field of microbicide development to combat HIV-1 sequence diversity and minimize the transmission of resistant variants. A combination of S-acyl-2-mercaptobenzamide thioester-10 (SAMT10), an inhibitor of the HIV-1 nucleocapsid protein (NCp7), and the fusion inhibitor sifuvirtide (SFT) may exert synergistic effects, since SFT can block viral fusion at an early stage of the viral cycle and SAMT10 can disrupt viral particles at a later stage. In this study, we investigated the effect of the combination of SAMT10 and SFT on HIV-1 infection using in vitro cell culture and ex vivo mucosal explant models. A range of doses for each compound was tested at 10-fold serial dilutions based on their 50% effective concentrations (EC). We observed a synergistic effect of SAMT10 and SFT in vitro against both the laboratory-adapted HIV-1 strain HIV-1 (subtype B, X4) and three pseudotyped viruses prevalent in Chinese sexually transmitted populations (SVPB16 (subtype B, R5), SVPC12 (subtype C, R5) and SH1.81 (CRF01_AE, R5)). In the ex vivo study, the EC values of the inhibitor combinations were reduced 1.5- to 2-fold in colorectal mucosal explants compared to treatment with SAMT10 or SFT alone by using with HIV-1. These results may provide a novel strategy for microbicide development against HIV-1 sexual transmission.
同时攻击多个靶点的策略在抗微生物药物开发领域值得探索，以应对HIV-1的序列多样性并尽量减少耐药变异体的传播。HIV-1核衣壳蛋白（NCp7）抑制剂S-酰基-2-巯基苯甲酰胺硫酯-10（SAMT10）与融合抑制剂西夫韦肽（SFT）联合使用可能会产生协同效应，因为SFT可在病毒周期早期阻断病毒融合，而SAMT10可在后期破坏病毒颗粒。在本研究中，我们使用体外细胞培养和离体黏膜外植体模型研究了SAMT10与SFT联合使用对HIV-1感染的影响。根据每种化合物的50%有效浓度（EC），以10倍系列稀释的方式测试了一系列剂量。我们观察到SAMT10与SFT在体外对实验室适应的HIV-1毒株HIV-1（B亚型，X4）以及中国性传播人群中流行的三种假型病毒（SVPB16（B亚型，R5）、SVPC12（C亚型，R5）和SH1.81（CRF01_AE，R5））均具有协同作用。在离体研究中，与单独使用SAMT10或SFT处理相比，在结肠黏膜外植体中，抑制剂组合与HIV-1一起使用时的EC值降低了1.5至2倍。这些结果可能为开发抗HIV-1性传播的抗微生物药物提供一种新策略。
