Laboratory Syntheses of Mycobacterial tuberculosis LAM Prototypes

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Tuberculosis, after several decades of control - at least in First World nations - is seeing a troubling resurgence, with strains that are proving to be multi-drug resistant (MDR) and, of late, extensively drug resistant (XDR). The BCG vaccine that worked so well for decades is no longer reliable. Synergy with HIV infection provides a looming, dismal prospect. The responsible agent, Mycobacterium tuberculosis, is protected, in part, by a fortress of oligosaccharides, an immunomodulatory sub-domain of which is lipoarabinomannan (LAM). In addition to TB, LAMs have been shown to be associated with diseases as varied as herpes, bladder cancer, HIV, allergic asthma and type I diabetes. Because of the virulence of M. tuberculosis, it has been impossible to assign the exact structure of its LAM, but "working" cartoons have been cobbled together from structural studies on less virulent mycobacteria. In spite of these structural uncertainties, biological roles have been assigned to the various sub-domains, notably, a variable component known as the "cap". Our lab has distilled information from various cartoons to obtain a working synthetic target of a LAM prototype, and with funding from the National Science Foundation, we have been able to explore relevant methodologies. Excellent progress, outlined in the preliminary work, augurs well for completing syntheses of LAM prototypes PUBLIC HEALTH RELEVANCE:Oligosaccharides, oligonucleotides and oligopeptides constitute the three oligomers that are implicated in biological processes, but while the last two have yielded to regular laboratory synthesis, the first continues to present daunting challenges. Under a grant from the National Science Foundation entitled "Telling glycosyl donors where to go" the PI and coworkers have developed strategies to overcome many of the obstacles, and have demonstrated validity by achieving the first laboratory syntheses of major domains of the complex immunoregulatory oligosaccharide glycolipid, known as a lipoarabinomannan (LAM). which is anchored to the external cell wall of Mycobacterial species, notably M. tuberculosis. LAM is part of a chemical fortress that protects the bacterium from external agents such as drugs, thereby inhibiting cures as well as diagnosis. Our preliminary synthetic work augurs well for completion of a total synthesis of LAM that will provide material of unquestioned authenticity for use in developing therapeutic agents.