MYCOBACTERIAL CELL ENVELOPE--A TARGET FOR NOVEL DRUGS AGAINST TUBERCULOSIS

这项研究计划目前正在SmithKline Beecham(SB)进行， Brockham Park，英格兰萨里郡，现在正式成为NCDDG的一部分 C0=业务协议，由项目负责人I.Chopra博士于#年撰写 与在英国的其他参与的SB工作人员一起。 分枝杆菌细胞膜，其中含有大量的复合体 脂肪和碳水化合物，特别是真菌酸、阿拉伯半乳糖和 脂阿拉伯甘露聚糖，是这些生物的高度特征。 为开发新的化疗药物提供了一个有吸引力的靶点 探员们。控制生物合成的潜在机制 阿拉伯半乳聚糖、阿拉伯甘露聚糖和霉菌酸现在 充分理解了新奇的目标导向型设计 干预策略是可行的。因此，建议 在这个项目的过程中，政务司司长的工作人员将遵循一些 具体途径侧重于抑制霉酚酸酯的生物合成。更多 具体地说，他们将：(I)基于14C- 加入醋酸盐，(Ii)开发第二代和第三代屏幕 与项目1和项目2结合使用部分纯化或纯化 蛋白质。对化合物资料库进行评估，并 天然产物从SB获得新型霉酚酸酯抑制剂 生物合成；(3)开发和利用结核分枝杆菌感染模型； (4)制定和实施全细胞和BACTEC筛查方案；(5) 在蛋白质分析和克隆策略方面为项目2提供支持； 最后，(6)探索X射线结晶学的可能用途。 分子模拟在开发新型治疗药物中的辅助作用 抗结核分枝杆菌药物。这一行业的共同努力 财团应与我们的学术界同事一起提供 新产品，与现有药物相结合，应该允许 一种更有效的结核病治疗方法。

This research program, currently under way at SmithKline Beecham (SB), Brockham Park, Surrey, England, which is now formally part of this NCDDG C0=operative Agreement, was written by the Project Leader, Dr. I. Chopra in conjunction with other participating SB staff in the United Kingdom. The mycobacterial cell envelope, which contains large amounts of complex lipids and carbohydrates, notably the mycolic acids, arabinogalactan and lipoarabinomannan, is highly characteristic of these organisms.This presents an attractive target for the development of new chemotherapeutic agents. The underlying mechanisms governing the biosynthesis of arabinogalactan, lipoarabinomannan and the mycolic acids are now sufficiently well understood that the design of novel target-directed intervention strategies is feasible. As a result, it is proposed that during the course of this program, CS staff will follow a number of concrete avenues focused on inhibition of mycolate biosynthesis. More specifically, they will: (i) optimize the primary screen based on 14C- acetate incorporation, (ii) develop second and third generation screens in conjunction with Projects 1 and 2 using partially purified or purified proteins. Conduct an evaluation of the chemical compounds library and natural product sources at SB for novel inhibitors of mycolate biosynthesis, (iii) develop and utilize M. tuberculosis infection models, (iv) develop and implement whole-cell and BACTEC screening protocols, (v) provide support to Project 2 in protein analysis and cloning strategies, and finally, (vi) exploit the possible use of X-ray crystallography/ molecular modelling as an aid in the development of novel therapeutic agents against M. tuberculosis. The combined efforts of this industrial consortium in conjunction with our colleagues from academia should provide novel products which, in combination with existing drugs, should allow for a more effective treatment of tuberculosis.