Kirschberg Thorsten, Parrish Jay
Gilead Sciences Inc, 333 Lakeside Drive, Foster City, CA 94404, USA.
Curr Opin Drug Discov Devel. 2007 Jul;10(4):460-72.
Processes involving the creation and modification of oligomeric nucleotide substrates are key events in the replication cycles of many viruses, and have been successful targets for much pharmaceutical research. Because of high levels of intracellular divalent magnesium, and the high affinity of oxyanions for this hard Lewis acid, enzymes responsible for these transformations have evolved to use the divalent magnesium cation in their catalytic function. The interruption of enzyme function via active-site metal coordination has recently emerged as a viable approach to viral inhibition, and the most advanced programs in this field have now entered late-stage clinical trials, thus validating the approach. This review summarizes such programs that were initiated from alpha,gamma-diketo acid leads and that resulted in optimized candidates. Key relationships between structure and activity for successful high-affinity magnesium binding in the active site of these enzymes have been identified.
涉及寡聚核苷酸底物的生成和修饰的过程是许多病毒复制周期中的关键事件，并且一直是许多药物研究的成功靶点。由于细胞内二价镁含量高，以及氧阴离子对这种硬路易斯酸的高亲和力，负责这些转化的酶已经进化为在其催化功能中使用二价镁阳离子。通过活性位点金属配位来中断酶功能最近已成为一种可行的病毒抑制方法，该领域最先进的项目现已进入后期临床试验，从而验证了该方法。本综述总结了从α,γ-二酮酸先导物开始并产生优化候选物的此类项目。已经确定了这些酶活性位点中成功实现高亲和力镁结合的结构与活性之间的关键关系。
