Rocha-Pereira J, Nascimento M S J, Ma Q, Hilgenfeld R, Neyts J, Jochmans D
L. Microbiologia, D. Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
L. Microbiologia, D. Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
Antimicrob Agents Chemother. 2014 Aug;58(8):4675-81. doi: 10.1128/AAC.02546-13. Epub 2014 Jun 2.
Potent and safe inhibitors of norovirus replication are needed for the treatment and prophylaxis of norovirus infections. We here report that the in vitro anti-norovirus activity of the protease inhibitor rupintrivir is extended to murine noroviruses and that rupintrivir clears human cells from their Norwalk replicon after only two passages of antiviral pressure. In addition, we demonstrate that rupintrivir inhibits the human norovirus (genogroup II [GII]) protease and further explain the inhibitory effect of the molecule by means of molecular modeling on the basis of the crystal structure of the Norwalk virus protease. The combination of rupintrivir with the RNA-dependent RNA polymerase inhibitors 2'-C-methylcytidine and favipiravir (T-705) resulted in a merely additive antiviral effect. The fact that rupintrivir is active against noroviruses belonging to genogroup I (Norwalk virus), genogroup V (murine norovirus), and the recombinant 3C-like protease of a GII norovirus suggests that the drug exerts cross-genotypic anti-norovirus activity and will thus most likely be effective against the clinically relevant human norovirus strains. The design of antiviral molecules targeting the norovirus protease could be a valuable approach for the treatment and/or prophylaxis of norovirus infections.
治疗和预防诺如病毒感染需要高效且安全的诺如病毒复制抑制剂。我们在此报告，蛋白酶抑制剂鲁平替尼的体外抗诺如病毒活性可扩展至鼠诺如病毒，并且在施加仅两轮抗病毒压力后，鲁平替尼就能使人类细胞中的诺沃克复制子清除。此外，我们证明鲁平替尼可抑制人诺如病毒（基因组II型[GII]）蛋白酶，并基于诺沃克病毒蛋白酶的晶体结构通过分子建模进一步解释该分子的抑制作用。鲁平替尼与RNA依赖性RNA聚合酶抑制剂2'-C-甲基胞苷和法匹拉韦（T-705）联合使用仅产生相加的抗病毒效果。鲁平替尼对属于基因组I型（诺沃克病毒）、基因组V型（鼠诺如病毒）的诺如病毒以及一种GII型诺如病毒的重组3C样蛋白酶具有活性，这一事实表明该药物具有跨基因型抗诺如病毒活性，因此很可能对临床相关的人类诺如病毒株有效。设计靶向诺如病毒蛋白酶的抗病毒分子可能是治疗和/或预防诺如病毒感染的一种有价值的方法。
