Structural Biology of TB Drug Targets

Texas A&M Agrilife Research, College Station TX

Investigators

Linked publications & trials

Abstract

The UCLA project develops and applies structural and bioinformatic tools for the discovery of protein drug targets and[unreadable] drugs against tuberculosis. We have developed the database for the TB Structural Genomics Consortium. This[unreadable] contains a wealth of information on the genome and proteome of Mycobacterium tuberculosis, which is open to[unreadable] researchers world wide to aid them in their structural studies of MTb proteins. Improvements to the database will[unreadable] enhance the ease with which scientists can view and update information about each protein. The information will[unreadable] include the complete history of experiments on each protein, as the project moves from cloning and expression, through[unreadable] purification, crystallization, structure determination, and drug discovery. The database will also incorporate new[unreadable] bioinformatics methods being developed at UCLA. These include methods for inferring the biological function of[unreadable] proteins from their structures by the server ProKnow and for inferring biological function from genome sequences from[unreadable] the database ProLinks. A new method for inferring biological function from combined genome sequences and[unreadable] microarray data will be developed to aid consortium members in selecting the most effective targets for structural[unreadable] studies in the effort to determine drugs.[unreadable] Structural studies of Mtb proteins at UCLA will focus on secreted, regulatory, and metabolic proteins. These proteins[unreadable] are involved in the invasion of host cells by Mtb, in the protection of Mtb against host cell defenses, in survival of Mtb[unreadable] and are thus potential protein drug targets. Secreted proteins of Mtb in particular are excellent anti- Mtb drug targets[unreadable] because drugs inhibiting these proteins do not have to penetrate the waxy cell wall of Mtb. Structures of each of these[unreadable] protein targets can then be screened in silico against ligands, in collaboration with Dr. James Sacchettini's laboratory.[unreadable] Predicted ligands will be co-crystallized for further structural studies. Potential inhibitors will be studied in collaboration[unreadable] with Dr. William Jacobs' laboratory to see if they prevent growth of Mtb within a mouse model.[unreadable] Each protein whose structure we determine, we will also characterize biochemically. Developing an in vitro assay will[unreadable] allow high-throughput in vitro drug screening, continuing our collaboration with the Southern Research Institute. All lead[unreadable] compounds will be cocrystallized with its target protein for structural studies. Where functions of proteins are unknown,[unreadable] our bioinformatics tools may predict a function, which will then be verified experimentally, to move the protein into the[unreadable] drug discovery pipeline. Dozens of MTb proteins are in the UCLA pipeline, with some half dozen at the stage of[unreadable] crystals.[unreadable]