小柯机器人

比利时Janssen制药公司Marnix Van Loock团队近期取得重要工作进展，他们研究发现阻断NS3–NS4B相互作用可以抑制非人类灵长类动物中的登革病毒。相关研究论文2023年3月15日在线发表于《自然》杂志上。

据介绍，登革热是一种主要的健康威胁，由四种登革热血清型引起的有症状感染人数估计为1/9600万，每年约有10000人死亡。然而，目前尚无抗病毒药物可用于登革热的治疗或预防。

研究人员最近描述了非结构蛋白NS3和NS4B之间的相互作用，这是开发泛血清型登革热病毒（DENV）抑制剂的一个有前途的靶点。研究人员提出了JNJ-1802（一种高效DENV抑制剂），它能阻断病毒复制复合物中NS3–NS4B的相互作用。JNJ-1802在小鼠中对四种DENV血清型中的任何一种的感染具有皮摩尔至低纳摩尔的体外抗病毒活性、高耐药性屏障和强大的体内疗效。最后，研究人员证明了小分子抑制剂JNJ-1802对非人类灵长类动物的DENV-1或DENV-2病毒感染非常有效。JNJ-1802在健康志愿者中成功完成了第一阶段人体临床研究，并被发现是安全和耐受的。

总之，这些发现支持了JNJ-1802的进一步临床开发，JNJ-1802是一种针对登革热的一流抗病毒药物，目前正在登革热预防和治疗的临床研究中取得进展。

附：英文原文

Title: Blocking NS3–NS4B interaction inhibits dengue virus in non-human primates

Author: Goethals, Olivia, Kaptein, Suzanne J. F., Kesteleyn, Bart, Bonfanti, Jean-Franois, Van Wesenbeeck, Liesbeth, Bardiot, Dorothe, Verschoor, Ernst J., Verstrepen, Babs E., Fagrouch, Zahra, Putnak, J. Robert, Kiemel, Dominik, Ackaert, Oliver, Straetemans, Roel, Lachau-Durand, Sophie, Geluykens, Peggy, Crabbe, Marjolein, Thys, Kim, Stoops, Bart, Lenz, Oliver, Tambuyzer, Lotke, De Meyer, Sandra, Dallmeier, Kai, McCracken, Michael K., Gromowski, Gregory D., Rutvisuttinunt, Wiriya, Jarman, Richard G., Karasavvas, Nicos, Touret, Franck, Querat, Gilles, de Lamballerie, Xavier, Chatel-Chaix, Laurent, Milligan, Gregg N., Beasley, David W. C., Bourne, Nigel, Barrett, Alan D. T., Marchand, Arnaud, Jonckers, Tim H. M., Raboisson, Pierre, Simmen, Kenny, Chaltin, Patrick, Bartenschlager, Ralf, Bogers, Willy M., Neyts, Johan, Van Loock, Marnix

Issue&Volume: 2023-03-15

Abstract: Dengue is a major health threat and the number of symptomatic infections caused by the four dengue serotypes is estimated to be 96million1 with annually around 10,000 deaths2. However, no antiviral drugs are available for the treatment or prophylaxis of dengue. We recently described the interaction between non-structural proteins NS3 and NS4B as a promising target for the development of pan-serotype dengue virus (DENV) inhibitors3. Here we present JNJ-1802—a highly potent DENV inhibitor that blocks the NS3–NS4B interaction within the viral replication complex. JNJ-1802 exerts picomolar to low nanomolar in vitro antiviral activity, a high barrier to resistance and potent in vivo efficacy in mice against infection with any of the four DENV serotypes. Finally, we demonstrate that the small-molecule inhibitor JNJ-1802 is highly effective against viral infection with DENV-1 or DENV-2 in non-human primates. JNJ-1802 has successfully completed a phase I first-in-human clinical study in healthy volunteers and was found to be safe and well tolerated4. These findings support the further clinical development of JNJ-1802, a first-in-class antiviral agent against dengue, which is now progressing in clinical studies for the prevention and treatment of dengue.

DOI: 10.1038/s41586-023-05790-6

Source: https://www.nature.com/articles/s41586-023-05790-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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