Glutamine Synthetase Inhibitors for Tuberculosis Therapy

性状（由申请方提供：）分枝杆菌感染 结核病（MBT）是许多艾滋病患者经历的重要并发症 患者最近，谷氨酰胺合成酶（GS）已经成为一种新的酶。 MTB的治疗靶点，由于证明了 酶活性MBT GS是生存和致病性所必需的。 有机体拟议研究的长期目标是开发抑制剂 具有潜在的治疗用途。许多体外细菌抑制剂 GS已经被记录，但没有一个在临床上有用。以便启动 MBT GS抑制剂设计，本提案的一部分旨在了解 其分子特性与已被广泛研究的E. coli GS.如果 与E.大肠杆菌GS，然后将采取新的策略， 比以前描述的任何抑制剂都更有效和选择性 化合物.具体地，GS的高度对称的环结构将是 利用它来设计多价抑制剂库， 与单价抑制剂相反， 以前单独针对活性位点。具体目标是：1） 为了确定是否结构修改的中心环上的每一个 亚基导致酶活性丧失。因为修改的 E.大肠杆菌GS确实会导致活性丧失，预计 这将是MBT GS的情况; 2）设计，合成和筛选 靶向MBT GS中心环的多价抑制剂文库， 和E. coli GS，用于“原理验证”。"证明 靶向MBT GS中心环的多价抑制剂将提供一种新的靶向抑制剂。 GS抑制和可能用于结核病治疗的新原理。

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.