Chen Eric, Swift Robert V, Alderson Nazilla, Feher Victoria A, Feng Gen-Sheng, Amaro Rommie E
Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, California, 92093. USA.
Department of Pathology, University of California San Diego, La Jolla, California, 92093. USA.
ACS Med Chem Lett. 2014 Jan 9;5(1):61-64. doi: 10.1021/ml4003474.
Influenza is a global human health threat, and there is an immediate need for new antiviral therapies to circumvent the limitations of vaccination and current small molecule therapies. During viral transcription, influenza incorporates the 5'-end of the host cell's mRNA in a process that requires the influenza endonuclease. Based on recently published endonuclease crystalized structures, a three-dimensional pharmacophore was developed and used to virtually screen 450,000 compounds for influenza endonuclease inhibitors. Of 264 compounds tested in a FRET-based endonuclease-inhibition assay, 16 inhibitors (IC <50 μM) that span 5 molecular classes novel to this endonuclease were found (6.1% hit rate). To determine cytotoxicity and antiviral activity, subsequent cellular assays were performed. Two compounds suppress viral replication with negligible cell toxicity.
流感是全球人类健康的一大威胁，当下迫切需要新的抗病毒疗法来克服疫苗接种和现有小分子疗法的局限性。在病毒转录过程中，流感病毒在一个需要流感内切酶的过程中整合宿主细胞mRNA的5'端。基于最近发表的内切酶晶体结构，开发了一种三维药效团，并用于虚拟筛选450,000种化合物以寻找流感内切酶抑制剂。在基于荧光共振能量转移（FRET）的内切酶抑制试验中测试的264种化合物中，发现了16种抑制剂（IC<50 μM），它们跨越了该内切酶的5个新分子类别（命中率为6.1%）。为了确定细胞毒性和抗病毒活性，随后进行了细胞试验。两种化合物能抑制病毒复制，且细胞毒性可忽略不计。
