3-Hydroxypyrimidine-2,4-diones as Selective Active Site Inhibitors of HIV Reverse Transcriptase-Associated RNase H: Design, Synthesis, and Biochemical Evaluations
作者:Jing Tang、Feng Liu、Eva Nagy、Lena Miller、Karen A. Kirby、Daniel J. Wilson、Bulan Wu、Stefan G. Sarafianos、Michael A. Parniak、Zhengqiang Wang
DOI:10.1021/acs.jmedchem.5b01879
日期:2016.3.24
achieve selective RNase H inhibition. Biochemical studies showed the two subtypes with an N-1 methyl group (9 and 10) inhibited RNase H in low micromolar range without siginificantly inhibiting RT polymerase, whereas the N-1 unsubstituted subtype 11 inhibited RNase H in submicromolar range and RT polymerase in low micromolar range. Subtype 11 also exhibited substantially reduced inhibition in the HIV-1
人类免疫缺陷病毒(HIV)逆转录酶(RT)相关的核糖核酸酶H(RNase H)仍然是未经验证的抗病毒靶标。特异性靶向HIV RNase H的主要挑战来自对RT聚合酶(pol)和整合酶(IN)链转移(ST)抑制作用的普遍缺乏选择性。我们在此报告了三种新颖的3-羟基嘧啶-2,4-二酮(HPD)亚型的合成和生化评估,这些亚型经过精心设计以实现选择性RNase H抑制。生化研究表明,具有N-1甲基的两个亚型(9和10)在低微摩尔范围内抑制RNase H,而未显着抑制RT聚合酶,而N-1未取代的亚型11在亚微摩尔范围内抑制RNase H,在低微摩尔范围内抑制RT聚合酶。亚型11在HIV-1 INST分析中也表现出明显降低的抑制作用,在细胞生存力分析中没有明显的细胞毒性,这表明它可能适合进一步的结构-活性关系(SAR),以鉴定具有抗病毒活性的RNase H抑制剂。