Coluccia Antonio, Puxeddu Michela, Nalli Marianna, Wei Chih-Ku, Wu Yu-Hsuan, Mastrangelo Eloise, Elamin Tasneem, Tarantino Delia, Bugert Joachim Jakob, Schreiner Benno, Nolte Juliane, Schwarze Frank, La Regina Giuseppe, Lee Jin-Ching, Silvestri Romano
Laboratory Affiliated to Institute Pasteur Italy - Cenci Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185 Rome, Italy.
Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
ACS Med Chem Lett. 2020 Jan 15;11(10):1869-1874. doi: 10.1021/acsmedchemlett.9b00405. eCollection 2020 Oct 8.
Zika virus (ZIKV) infection, which initially was endemic only in Africa and Asia, is rapidly spreading throughout Europe, Oceania, and the Americas. Although there have been enormous efforts, there is still no approved drug to treat ZIKV infection. Herein, we report the synthesis and biological evaluation of agents with noncompetitive mechanism of the ZIKV NS2B/NS3 protease inhibition through the binding to an allosteric site. Compounds and showed potent activity in both enzymatic and cellular assays. Derivative efficiently reduced the ZIKV protein synthesis and the RNA replication and prevented the mice from life-threatening infection and the brain damage caused by ZIKV infection in a ZIKV mouse model.
寨卡病毒（ZIKV）感染最初仅在非洲和亚洲流行，目前正在欧洲、大洋洲和美洲迅速传播。尽管已经付出了巨大努力，但仍没有获批用于治疗ZIKV感染的药物。在此，我们报告了通过结合变构位点对ZIKV NS2B/NS3蛋白酶具有非竞争性抑制机制的药物的合成及生物学评价。化合物 和 在酶促和细胞试验中均表现出强效活性。在寨卡病毒小鼠模型中，衍生物 有效减少了ZIKV蛋白合成和RNA复制，并防止小鼠因ZIKV感染而危及生命和造成脑损伤。
