Identification of aryl dihydrouracil derivatives as palm initiation site inhibitors of HCV NS5B polymerase

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• 作者：Yaya Liu ; ^{yaya.liu@abbott.com} ; Ben Hock Lim ; Wen W. Jiang ; Charles A. Flentge ; Douglas K. Hutchinson ; Darold L. Madigan ; John T. Randolph ; Rolf Wagner ; Clarence J. Maring ; Warren M. Kati ; Akhteruzzaman Molla
• 关键词：Hepatitis C ; HCV ; HCV NS5B polymerase ; Antiviral
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：1 June, 2012
• 年：2012
• 卷：22
• 期：11
• 页码：3747-3750
• 全文大小：474 K

文摘

Aryl dihydrouracil derivatives were identified from high throughput screening as potent inhibitors of HCV NS5B polymerase. The aryl dihydrouracil derivatives were shown to be non-competitive with respect to template RNA and elongation nucleotide substrates. They demonstrated genotype 1 specific activity towards HCV NS5B polymerases. Structure activity relationships and genotype specific activities of aryl dihydrouracil derivatives suggested that they bind to the palm initiation nucleotide pocket, a hypothesis which was confirmed by studies with polymerases containing mutations in various inhibitor binding sites. Therefore, aryl dihydrouracil derivatives represent a novel class of palm initiation site inhibitors of HCV NS5B polymerase.