Small molecule functional analogs of peptides that inhibit λ site-specific recombination and bind Holliday junctions
Small molecule functional analogs of peptides that inhibit λ site-specific recombination and bind Holliday junctions
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DOI：
10.1016/j.bmcl.2010.06.029
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发表时间：
2010-08-01
影响因子：
2.7
通讯作者：
Segall, Anca M.
中科院分区：
文献类型：
--
作者：
Ranjit, Dev K.;Rideout, Marc C.;Segall, Anca M.
我们的实验室已经分离出六聚肽，它们是Holliday连接(HJ)的结构选择配体，是几种DNA重组反应的中心中间体。其中最有效的抑制剂之一，WRWYCR，已经显示出抗菌活性，部分原因是它抑制DNA修复蛋白。为了增加这些抑制剂的治疗潜力，我们寻找具有相似活性的小分子抑制剂。我们筛选了11个小分子文库，包括900多万个单独的化合物，并确定了一种有效的N-甲氨基环硫脲抑制剂，它也可以捕获在体外特定部位重组反应中形成的HJS。这种抑制剂能与无蛋白的HJS特异结合，并能通过RecG解旋酶抑制HJ的拆分，但对有高通透性外膜的细菌只表现出温和的生长抑制作用；然而，这是开发多肽抑制剂功能类似物的重要一步。(C)2010爱思唯尔有限公司。保留所有权利。
Our lab has isolated hexameric peptides that are structure-selective ligands of Holliday junctions (HJ), central intermediates of several DNA recombination reactions. One of the most potent of these inhibitors, WRWYCR, has shown antibacterial activity in part due to its inhibition of DNA repair proteins. To increase the therapeutic potential of these inhibitors, we searched for small molecule inhibitors with similar activities. We screened 11 small molecule libraries comprising over nine million individual compounds and identified a potent N-methyl aminocyclic thiourea inhibitor that also traps HJs formed during site-specific recombination reactions in vitro. This inhibitor binds specifically to protein-free HJs and can inhibit HJ resolution by RecG helicase, but only showed modest growth inhibition of bacterial with a hyperpermeable outer membrane; nonetheless, this is an important step in developing a functional analog of the peptide inhibitors. (C) 2010 Elsevier Ltd. All rights reserved.