INHA WITH INHIBITORS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 INHA是参与结核分枝杆菌II型脂肪酸生物合成(Fas II)的Enoyl-acyl载体蛋白还原酶。目前的结核病药物异烟肼已被证明以INHA为靶点，来自其他生物的许多Fas II烯酰基还原酶也是有效的药物靶点。我们团队开发的新型INHA抑制剂利用了与INH不同的抑制机制，可以绕过INH耐药性，它们是慢结合抑制剂，由于滞留时间长，有望在体内表现出更好的疗效。我们正在使用结晶学来研究缓慢抑制的结构基础。将研究InHA底物结合环的有序性和构象与结合动力学的相关性，这些信息将被用于设计具有更好结合动力学的抑制剂。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. InhA is the enoyl-acyl carrier protein reductase involved in type II fatty acid biosynthesis (FAS II) of Mycobacterium tuberculosis. The current TB drug INH has been shown to target InhA, and many FAS II enoylreductases from other organisms are also validated drug targets. The novel InhA inhibitors developed in our group utilize a different mechanism of inhibition from INH and can bypass INH resistance, and they are slow binding inhibitors that are expected to show better in vivo efficacy because of long residence time. We are using crystallography to study the structural basis of slow inhibition. Correlation of ordering and conformation of the InhA substrate binding loop with binding kinetics will be investigated and such information will be used for designing inhibitors with better binding kinetics.