Targeting the Host to Treat TB: Inhibitors of Protein Kinase R

描述(申请人提供)：结核病是一种可治愈的传染病的唯一主要死亡原因，由于耐药性的传播，它正逐渐变得无法治愈。这个项目探索了一种解决结核分枝杆菌(Mtb)对抗感染药物耐药性的方法：抑制宿主中的蛋白激酶R(PKR)。MTB依赖PKR导致全面疾病。我们最近发现，感染Mtb的PKR缺陷小鼠显著减少了细菌负担和组织病理学。其机制涉及PKR抑制巨噬细胞受干扰素-γ(IFN？)经典激活的程度。和微生物产品。PKR通过连接干扰素？抑制巨噬细胞活化产生少量的白介素10(IL10)，这是一种巨噬细胞失活因子。我们发现了一种新的PKR抑制剂，它能在有干扰素存在的情况下弥补PKR缺陷而产生巨噬细胞的“超激活”。还是干扰素的组合？和结核分枝杆菌，表现为IL10的产生减少，一氧化氮和肿瘤坏死因子(TNF)的产生增加。小分子巨噬细胞超激活因子(SAM)可以为慢性感染的治疗提供一种新的辅助方法，而不存在选择病原体耐药性的可能性。我们将探索Celgene广泛的激酶抑制剂文库，以确定有效的、相对选择性的PKR抑制剂，并在体外和感染结核分枝杆菌的小鼠中将它们表征为SAM。

DESCRIPTION (provided by applicant): Tuberculosis is the single leading cause of death from a curable infectious disease and is becoming progressively incurable due to the spread of drug resistance. This project explores a work-around for resistance of M. tuberculosis (Mtb) to anti-infectives: inhibiting protein kinase R (PKR) in the host. Mtb depends on PKR to cause full-blown disease. We recently discovered that PKR-deficient mice infected with Mtb have markedly reduced bacterial burden and histopathology. The mechanism involves PKR's ability to restrain the extent to which macrophages undergo classical activation by interferon-gamma (IFN?) and microbial products. PKR restrains macrophage activation by linking IFN? signaling to the production of small amounts of interleukin-10 (IL10), a macrophage de-activating factor. We identified a novel inhibitor of PKR that phenocopied PKR deficiency in producing "super-activation" of macrophages in the presence of IFN? or the combination of IFN? and Mtb, as reflected by reduced production of IL10 and elevated production of nitric oxide and tumor necrosis factor (TNF). Small-molecule super-activators of macrophages (SAMs) could offer a novel, adjunctive approach to the treatment of chronic infections without the potential for selection of drug-resistance in the pathogen. We will explore Celgene's extensive library of kinase inhibitors to identify potent, relatively selective inhibitors of PKR and characterize them as SAMs in vitro and in Mtb-infected mice.