GLYCOSYLTRANSFERASES AS DRUG TARGETS IN MYCOBACTERIA

描述：（改编自申请人摘要）分枝杆菌细胞壁 合成是分枝杆菌发病机制中潜在的干预点。 研究人员将设计和合成分枝杆菌抑制剂， 酶rhap和galf（两者都不存在于哺乳动物细胞中）。具体地说， 分枝杆菌鼠李糖基的糖基供体和受体类似物， 利用核苷二磷酸糖供体的半乳糖基转移酶 UDP-呋喃半乳糖和TDP-吡喃鼠李糖。此外，调查人员将 在糖的受体位点结合并抑制的二糖 转移酶将使用肉汤稀释法在体外筛选这些化合物 测定和无细胞测定转移酶。选择的活性化合物将 在巨噬细胞测定和鼠TB模型中体外和体内筛选， 分别

DESCRIPTION: (Adapted from Applicant's Abstract) Mycobacterial cell wall synthesis is a potential point of intervention in mycobacterial pathogenesis. The investigators will design and synthesize inhibitors of mycobacterial enzymes rhap and galf (neither are found in mammalian cells). Specifically, glycosyl donor and acceptor analogs of mycobacterial rhamnosyl- galactosyltransferases that utilize nucleoside diphosphate sugar donors UDP-galactofuranose and TDP-rhamnopyranose. Also, the investigators will make disaccharides that bind and inhibit in the acceptor site of the sugar transferases. These compounds will be screened in vitro using a broth dilution assay and cell-free assay transferase. Selected active compounds will be screened in vitro and in vivo in a macrophage assay and a murine TB model, respectively.