Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Inage-ku, Chiba, Japan.
J Med Chem. 2009 Mar 12;52(5):1380-7. doi: 10.1021/jm801071m.
The RNase H activity associated with human immunodeficiency virus type 1 (HIV-1) is an attractive target for an antiretroviral drug development. We screened 20000 small-molecular-weight compounds for RNase H inhibitors and identified a novel RNase H-inhibiting structure characterized by a 5-nitro-furan-2-carboxylic acid carbamoylmethyl ester (NACME) moiety. Two NACME derivatives, 5-nitro-furan-2-carboxylic acid adamantan-1-carbamoylmethyl ester (compound 1) and 5-nitro-furan-2-carboxylic acid [[4-(4-bromo-phenyl)-thiazol-2-yl]-(tetrahydro-furan-2-ylmethyl)-carbamoyl]-methyl ester (compound 2), effectively blocked HIV-1 and MLV RT-associated RNase H activities with IC(50)s of 3-30 microM but had little effect on bacterial RNase H activity in vitro. Additionally, 20-25 microM compound 2 effectively inhibited HIV-1 replication. An in silico docking simulation indicated that the conserved His539 residue, and two metal ions in the RNase H catalytic center are involved in RNase H inhibition by NACME derivatives. Taken together, these data suggest that NACME derivatives may be potent lead compounds for development of a novel class of antiretroviral drugs.
人类免疫缺陷病毒 1 型（HIV-1）的核糖核酸酶 H 活性是抗逆转录病毒药物开发的一个有吸引力的靶点。我们筛选了 20000 种小分子化合物以寻找核糖核酸酶 H 抑制剂，并鉴定出一种新型的核糖核酸酶 H 抑制结构，其特征是 5-硝基-糠酸氨甲酰甲酯（NACME）部分。两种 NACME 衍生物，5-硝基-糠酸金刚烷-1-氨甲酰甲酯（化合物 1）和 5-硝基-糠酸[[4-（4-溴苯基）-噻唑-2-基]-（四氢呋喃-2-基甲基）-氨甲酰基]-甲酯（化合物 2），有效地阻断了 HIV-1 和 MLV RT 相关的核糖核酸酶 H 活性，IC50 为 3-30 μM，但对体外细菌核糖核酸酶 H 活性几乎没有影响。此外，20-25 μM 的化合物 2 有效地抑制了 HIV-1 的复制。计算机对接模拟表明，保守的 His539 残基和核糖核酸酶 H 催化中心的两个金属离子参与了 NACME 衍生物对核糖核酸酶 H 的抑制作用。综上所述，这些数据表明，NACME 衍生物可能是开发新型抗逆转录病毒药物的潜在有效先导化合物。
