Sun H, Zhi C, Wright G E, Ubiali D, Pregnolato M, Verri A, Focher F, Spadari S
Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA.
J Med Chem. 1999 Jul 1;42(13):2344-50. doi: 10.1021/jm980718d.
We recently reported the properties of the first selective inhibitors of herpes simplex virus type 1 (HSV1) uracil-DNA glycosylase (UDG), an enzyme of DNA repair that has been proposed to be required for reactivation of the virus from latency. 6-(4-Octylanilino)uracil (octAU) was the most potent inhibitor among a series of 6-(4-alkylanilino)uracils, acting in the micromolar range and without effect against human UDG. A 28.5-kDa catalytic fragment of HSV1 UDG has been crystallized in the presence of uracil, and the structure was recently solved. We have used the coordinates of this structure in order to study interaction of our inhibitors with the enzyme, and a model of binding between octAU and UDG has been derived. Starting with the optimized model, the activity of several octAU analogues was predicted, and the values compared favorably with experimental results found for the synthetic compounds. Several hydrophilic derivatives were predicted and found to be active as UDG inhibitors. These compounds will be useful to determine if UDG, like the viral thymidine kinase, is required for reactivation of HSV1 from latency in nerve cells.
我们最近报道了首个单纯疱疹病毒1型（HSV1）尿嘧啶-DNA糖基化酶（UDG）选择性抑制剂的特性，UDG是一种DNA修复酶，据推测它是病毒从潜伏状态重新激活所必需的。6-（4-辛基苯胺基）尿嘧啶（octAU）是一系列6-（4-烷基苯胺基）尿嘧啶中最有效的抑制剂，其作用于微摩尔范围，且对人UDG无影响。HSV1 UDG的一个28.5 kDa催化片段已在尿嘧啶存在下结晶，其结构最近已解析出来。我们利用该结构的坐标来研究抑制剂与酶的相互作用，并得出了octAU与UDG之间的结合模型。从优化模型出发，预测了几种octAU类似物的活性，其数值与合成化合物的实验结果相比很理想。预测并发现了几种亲水性衍生物作为UDG抑制剂具有活性。这些化合物将有助于确定UDG是否像病毒胸苷激酶一样，是HSV1从神经细胞潜伏状态重新激活所必需的。
