Glutamine Synthetase Inhibitors for Tuberculosis Therapy

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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.