MYCOBACTERIUM TUBERCULOSIS VIRULENCE FACTORS, PROTEIN TYROSINE PHOSPHATASES PTPA

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 自20世纪60年代初以来，没有开发出任何新的结核病药物。多重耐药菌株的出现和目前治疗的长持续时间（6个月）使得新药的设计至关重要。结核病的病原体，结核分枝杆菌（Mtb），产生两种蛋白酪氨酸磷酸酶（PTP），PtpA和PtpB。这些PTP被分泌到宿主巨噬细胞中，在那里它们破坏宿主免疫功能。PTP正在成为一类新的和有前途的药物靶点。Mtb PTP是特别易处理的靶标，因为它们可以在构成小分子高度不可渗透屏障的Mtb细胞外靶向。我们已经确定了特定的抑制剂PtpA和PtpB的亲和力在低微摩尔范围内。为了指导这些抑制剂的迭代改进，PTP与这些抑制剂在最高分子分辨率下的共晶结构将是必不可少的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. No new drugs against tuberculosis have been developed since the early 1960s. The emergence of multiple drug resistant strains and the long duration of current therapies (6 months) make the design of novel drugs crucial. The causative agent of tuberculosis, Mycobacterium tuberculosis (Mtb), produces two protein tyrosine phosphatases (PTPs), PtpA and PtpB. These PTPs are secreted into the host macrophage, where they subvert host immune functions. PTPs are emerging as a new and promising class of drug targets. The Mtb PTPs are particularly tractable targets because they can be targeted outside the Mtb cell coat that constitutes a highly impermeable barrier for small molecules. We have identified specific inhibitors of PtpA and PtpB with affinities in the low micromolar range. To guide the iterative improvement of these inhibitors, cocrystal structures of the PTPs with these inhibitors at the highest molecular resolution will be essential.