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

描述（由申请人提供）：结核病是可治愈的传染病导致死亡的唯一主要原因，由于耐药性的传播，结核病正逐渐变得不可治愈。该项目探索了一种解决M.结核病（Mtb）的抗感染药物：抑制宿主中的蛋白激酶R（PKR）。结核分枝杆菌依赖PKR引起全面疾病。我们最近发现，PKR缺陷小鼠感染结核分枝杆菌显着减少细菌负荷和组织病理学。该机制涉及PKR抑制巨噬细胞通过干扰素γ（IFN？）和微生物产品。PKR通过连接IFN？产生少量的白细胞介素-10（IL-10），一种巨噬细胞失活因子。我们确定了一种新的PKR抑制剂，phenocopied PKR缺陷产生的“超级激活”的巨噬细胞在IFN？还是IFN的组合？和Mtb，如通过减少的IL 10产生和升高的一氧化氮和肿瘤坏死因子（TNF）产生所反映的。小分子巨噬细胞超活化剂（SAM）可以提供一种新的，预防性的方法来治疗慢性感染，而没有潜在的选择耐药性的病原体。我们将探索Celgene的广泛的激酶抑制剂库，以确定有效的，相对选择性的PKR抑制剂，并在体外和结核分枝杆菌感染的小鼠中将其表征为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.