Glutamine Synthetase Inhibitors for Tuberculosis Therapy

描述(由申请人提供：)分枝杆菌感染 结核病(MBT)是许多艾滋病人经历的一种重要并发症 病人。近年来，谷氨酰胺合成酶(GS)已成为一种新的 结核分枝杆菌的治疗靶点，因为证明了 具有酶活性的MBTGS是该菌生存和致病所必需的 有机体。这项拟议研究的长期目标是开发抑制剂。 具有潜在治疗用途的MBT GS。许多细菌的体外抑制剂 GS已经被记录在案，但没有一种在临床上有用。为了发起 MBT GS抑制剂的设计，本提案的一部分旨在了解 它的分子性质，与研究较好的E.ColiGS。如果 可与E.ColiGS相媲美，那么将采取新的策略来获得 比以前描述的任何一种更有效和更有选择性的抑制剂 化合物。具体地说，GS的高度对称的环结构将是 被用来设计一个多价抑制剂的文库，该文库与 几个亚基上的柔性环，与单价抑制剂相反 之前针对活动站点的单独目标。具体目标是：1) 以确定是否对每个对象的中心环进行结构修改 亚基导致酶活性丧失。因为对 预计，大肠杆菌GS的中心环确实会导致活性丧失 这将是MBT GS的情况；2)设计、合成和筛选 靶向MBT GS中央环的多价抑制剂文库， 对于E.coliGS来说，这是一种“原则性证明”。演示了 针对MBT GS中央环的多价抑制剂将提供一种 抑制GS和可能用于结核病治疗的新理论基础。

DESCRIPTION (Provided by the applicant:) Infection by Mycobacterium tuberculosis (MBT) is a significant complication experienced by many AIDS patients. Recently, the enzyme glutamine synthetase (GS) has become a new therapeutic target for MTB, due to the demonstration that secretion of enzymatically active MBT GS is required for survival and pathogenecity of the organism. The long-term goal of the proposed research is to develop inhibitors of MBT GS with potential therapeutic use. Many in vitro inhibitors of bacterial GS's have been documented, but none are useful clinically. In order to initiate MBT GS inhibitor design, a portion of this proposal is aimed at understanding its molecular properties, in comparison to the well studied E. coli GS. If comparable to the E. coli GS, then a new strategy will be pursued to obtain inhibitors that are more potent and selective than any previously described compounds. Specifically, the highly symmetrical ring structure of GS will be exploited to design a library of multivalent inhibitors which bind to the flexible loop on several subunits, in contrast to the monovalent inhibitors previously targeted individually to the active sites. The specific aims are: 1) To determine whether structural modification of the central loop on each subunit results in loss of enzyme activity. Because the modification of the central loop of the E. coli GS does lead to loss of activity, it is anticipated that this will be the case for MBT GS; 2) To design, synthesize and screen libraries of multivalent inhibitors targeted to the central loops of MBT GS, and to E. coli GS, for 'proof-of-principle.' Demonstration of the utility of multivalent inhibitors targeted to the central loops of MBT GS would provide a new rationale for GS inhibition and possibly for tuberculosis therapy.