Li Fang, Ma Chunlong, Hu Yanmei, Wang Yuanxiang, Wang Jun
Department of Pharmacology and Toxicology, College of Pharmacy, and BIO5 Institute, The University of Arizona , Tucson, Arizona 85721, United States.
ACS Infect Dis. 2016 Oct 14;2(10):726-733. doi: 10.1021/acsinfecdis.6b00130. Epub 2016 Sep 22.
Despite the existence of flu vaccines and small-molecule antiviral drugs, influenza virus infection remains a public health concern that warrants immediate attention. As resistance to the only orally bioavailable drug, oseltamivir, has been continuously reported, there is a clear need to develop the next-generation of anti-influenza drugs. We chose the influenza A virus M2-S31N mutant proton channel as the drug target to address this need as it is one of the most conserved viral proteins and persist in >95% of currently circulating influenza A viruses. In this study, we report the development of a late-stage diversification strategy for the expeditious synthesis of M2-S31N inhibitors. The channel blockage and antiviral activity of the synthesized compounds were tested in two-electrode voltage clamp assays and antiviral assays, respectively. Several M2-S31N inhibitors were identified to have potent M2-S31N channel blockage and micromolar antiviral efficacy against several M2-S31N-containing influenza A viruses.
尽管存在流感疫苗和小分子抗病毒药物，但流感病毒感染仍然是一个需要立即关注的公共卫生问题。由于对唯一口服生物可利用药物奥司他韦的耐药性不断被报道，显然有必要开发下一代抗流感药物。我们选择甲型流感病毒M2 - S31N突变质子通道作为药物靶点来满足这一需求，因为它是最保守的病毒蛋白之一，并且存在于目前超过95%正在传播的甲型流感病毒中。在本研究中，我们报告了一种用于快速合成M2 - S31N抑制剂的后期多样化策略的开发。分别在双电极电压钳测定法和抗病毒测定法中测试了合成化合物的通道阻断和抗病毒活性。鉴定出几种M2 - S31N抑制剂对几种含M2 - S31N的甲型流感病毒具有有效的M2 - S31N通道阻断作用和微摩尔级抗病毒效力。
