Furin Inhibition in HIV Disease

描述（由申请人提供）：HIV包膜糖蛋白前体gp 160被细胞蛋白酶弗林蛋白酶和弗林蛋白酶样前蛋白转化酶（PPC）切割成成熟形式gp 120和gp 41。在本申请中，我们将探索PPC抑制作为HIV感染治疗的潜力。待检验的假设是，PPC抑制剂的抗HIV作用可以在不引起不良副作用的水平下获得。这将在细胞水平和完整动物中进行测试。我们将提供证据表明，稳定的小分子PPC抑制剂，六和九-D-精氨酸（D 6 R和D9 R），可以抑制HIV感染在组织培养中的传播，其浓度不影响细胞过程，并且在另一种模型中，D 6 R可以在体内用于防止假单胞菌外毒素A和炭疽毒素的裂解。这些研究表明，D 6 R和D9 R可用于治疗HIV感染。为了研究抑制PPC对HIV感染的影响，我们提出了两个具体目标。 1.检测D 6 R和D9 R对HIV感染的体外传播和Env处理的有效性。 2.在HIV感染的SCID小鼠模型中测试PPC抑制剂。 这些研究与抗病毒疗法的开发以及弗林蛋白酶和PPC作用发挥病理作用的其他病症的治疗相关。这些研究也将有助于阐明艾滋病毒利用其所居住的细胞的基本过程。

DESCRIPTION (provided by applicant): The HIV envelope glycoprotein precursor, gpl60, is cleaved into the mature forms, gp120 and gp41, by the cellular protease furin and furin-like proprotein convertases (PPCs). In this application, we will explore the potential of PPC inhibition as a therapy for HIV infection. The hypothesis to be tested is that anti-HIV effects of PPC inhibition can be obtained at levels that do not cause untoward side effects. This will be tested at both the cellular level and in intact animals. We will present evidence that stable, small molecule PPC inhibitors, hexa and nona-D-arginine (D6R and D9R), can inhibit the spread of HIV infection in tissue culture in concentrations that do not affect cellular processes, and in another model that D6R can be used in vivo to prevent the cleavage of pseudomonas exotoxin A and anthrax toxin. These studies suggest that D6R and D9R may be used to treat HIV infection. To study the effects of inhibiting PPCs on HIV infection, we propose two specific aims. 1. To test the efficacy of D6R and D9R on in vitro spread of HIV infection and Env processing. 2. To test PPC inhibitors in a SCID-mouse model of HIV infection. These studies have relevance for the development of antiviral therapies, as well as treatments for other conditions in which furin and PPC action plays a pathological role. These studies will also help elucidate basic processes by which HIV utilizes the cell it inhabits.