Identification of aryl dihydrouracil derivatives as palm initiation site inhibitors of HCV NS5B polymerase
- 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
- 期刊代码：10_0960894x
- 类别：ch
- 出版时间：1 June, 2012
- 卷：22
- 期：11
- 页码：3747-3750
- 文件大小：474 K
摘要
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.