Gustave Roussy Institute, Paris Saclay University, UMR8200 CNRS , 94805 Villejuif , France.
Aix Marseille University, INSERM, INRA, NORT, UMR 1260/1062 , 13007 Marseille , France.
J Med Chem. 2018 Aug 23;61(16):7202-7217. doi: 10.1021/acs.jmedchem.8b00557. Epub 2018 Aug 3.
The nucleoprotein (NP) of influenza A virus (IAV) required for IAV replication is a promising target for new antivirals. We previously identified by in silico screening naproxen being a dual inhibitor of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory effects. However, the recently shown strong COX2 antiviral potential makes COX2 inhibition undesirable. Here we designed and synthesized two new series of naproxen analogues called derivatives 2, 3, and 4 targeting highly conserved residues of the RNA binding groove, stabilizing NP monomer without inhibiting COX2. Derivative 2 presented improved antiviral effects in infected cells compared to that of naproxen and afforded a total protection of mice against a lethal viral challenge. Derivative 4 also protected infected cells challenged with circulating 2009-pandemic and oseltamivir-resistant H1N1 virus. This improved antiviral effect likely results from derivatives 2 and 4 inhibiting NP-RNA and NP-polymerase acidic subunit PA N-terminal interactions.
流感 A 病毒（IAV）复制所必需的核蛋白（NP）是新型抗病毒药物的有前途的靶标。我们之前通过计算机筛选发现，萘普生是 NP 和环氧化酶 COX2 的双重抑制剂，从而兼具抗病毒和抗炎作用。然而，最近发现 COX2 具有很强的抗病毒潜力，因此抑制 COX2 并不理想。在这里，我们设计并合成了两个新的萘普生类似物系列，称为衍生物 2、3 和 4，它们针对 RNA 结合槽的高度保守残基，稳定 NP 单体而不抑制 COX2。与萘普生相比，衍生物 2 在感染细胞中表现出更好的抗病毒效果，并能完全保护小鼠免受致命病毒攻击。衍生物 4 还能保护感染细胞免受循环 2009 年大流行和奥司他韦耐药 H1N1 病毒的挑战。这种改善的抗病毒作用可能是由于衍生物 2 和 4 抑制 NP-RNA 和 NP-聚合酶酸性亚基 PA N 端相互作用所致。
