Furin Inhibition in HIV Disease

描述（由申请人提供）：HIV包膜糖蛋白前体gpl60被细胞蛋白酶furin和furin样蛋白转化酶（PPCs）裂解为成熟形式gp120和gp41。在这个应用中，我们将探索PPC抑制作为HIV感染治疗的潜力。要验证的假设是，PPC抑制的抗hiv效果可以在不引起不良副作用的水平上获得。这将在细胞水平和完整的动物身上进行测试。我们将提供证据表明，稳定的小分子PPC抑制剂，hexa和nona- d -精氨酸（D6R和D9R）可以在不影响细胞过程的浓度下抑制组织培养中HIV感染的传播，并且在另一个模型中，D6R可以在体内用于阻止假单胞菌外毒素A和炭疽毒素的裂解。这些研究表明，D6R和D9R可能用于治疗HIV感染。为了研究抑制PPCs对HIV感染的影响，我们提出了两个具体目标。

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.