Furin Inhibition in HIV Disease

描述(由申请人提供)：HIV包膜糖蛋白前体gp60被细胞蛋白酶Furin和Furin样原蛋白转换酶(PPC)切割成成熟形式gp120和gp41。在这项应用中，我们将探索PPC抑制作为HIV感染治疗的潜力。需要检验的假设是，PPC抑制的抗HIV效果可以在不会引起不良副作用的水平上获得。这将在细胞水平和完好的动物身上进行测试。我们将提出证据表明，稳定的小分子PPC抑制剂，六甲和诺纳-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艾滋病毒感染的传播，并在另一个模型中，D6R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，D6R和D9R可能用于治疗HIV感染。为了研究抑制PPC对HIV感染的影响，我们提出了两个特定的目标。 1.检测D6R和D9R对HIV感染的体外传播和包膜加工的效果。 2.在HIV感染的SCID小鼠模型中测试PPC抑制剂。 这些研究对抗病毒疗法的开发以及对呋喃和PPC作用起病理性作用的其他疾病的治疗都有意义。这些研究还将有助于阐明艾滋病毒利用其所在细胞的基本过程。

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.