Small-Molecule Fusion Inhibitors Targeting a Fusion Intermediate State of HIV-1 g

描述(申请人提供)：高效抗逆转录病毒疗法(HAART)已将HIV-1感染从曾经的致命疾病转变为可控制的慢性疾病。最新的HAART方案使用了几种类别的抗病毒疗法，典型的疗法需要至少两种类别的三种或更多药物的组合。耐药性、严重的副作用和治疗依从性的困难给HAART的临床实施带来了挑战，表明需要更多的分子靶点。HIV-1感染的第一个关键步骤是由病毒包膜糖蛋白介导的病毒与靶细胞膜的融合。T20/恩福韦肽是第一个也是目前唯一批准的融合抑制剂 美国食品和药物管理局。与基于多肽的药物相关的局限性以及耐药病毒的快速出现限制了其长期使用。因此，一个理想的目标是开发口服可用小分子融合抑制剂，克服基于多肽的药物的局限性，并增加HAART治疗药物的可用类别范围。包膜糖蛋白gp41的瞬时构象被HIV-1融合抑制剂和某些中和抗体靶向，例如第一个被批准的进入抑制抗病毒药物T-20/enfuvitide。在这 项目中，我们假设HIV-1 gp41是一个“可药物”的靶点，我们可以为其开发小分子融合抑制剂来阻止其病毒进入所需的结构重排。我们进一步假设，小分子化合物可以模拟基于多肽的抗病毒药物或中和抗体，以阻止gp41功能和预防HIV-1感染。我们将把HIV-1研究中疫苗方面的最新进展带入寻找新的治疗方法。该项目完成后，不仅将产生用于临床测试的候选药物，还将为进一步剖析HIV-1进入的分子机制提供新的试剂。我们将追求以下具体目标：1)我们将开发一个基于结构的平台，用于优化针对HIV-1 gp41疏水口袋的小分子融合抑制剂；2)我们将生产针对gp41口袋的有效先导化合物；3)我们将确定针对HIV-1 gp41的MPER的小分子融合抑制剂。

DESCRIPTION (provided by applicant): Highly active antiretroviral therapy (HAART) has transformed HIV-1 infection, once a fatal illness, to a manageable chronic condition. The latest HAART regimen uses several classes of antiviral therapeutics and a typical therapy requires a combination of three or more drugs from at least two classes. Drug resistance, severe side effects and difficulties in treatment compliance have brought challenges to the implementation of HAART in clinical settings and indicate the need for additional molecular targets. The first critical step of HIV-1 infection is fusion of viral and target cell membranes mediated by viral envelope glycoprotein. T20/Enfuvirtide is the first and still the only fusion inhibitor approved by FDA. Limitations associated with peptide-based drugs as well as rapid emergence of resistant viruses have restricted its long-term use. A desirable goal is therefore to develop orally availabl small-molecule fusion inhibitors, to overcome the limitations of peptide-based drugs and to increase the range of available classes of HAART therapeutics. A transient conformational state of envelope glycoprotein gp41 is targeted by HIV-1 fusion inhibitors, such as T-20/Enfuvirtide - the first approved entry-inhibiting antiviral drug, and by certain neutralizing antibodies. In this project, we hypothesize that HIV-1 gp41 is a "druggable" target for which we can develop small-molecule fusion inhibitors to block its structural rearrangements required for viral entry. We further hypothesize that small-molecule compounds can mimic peptide-based antiviral drugs or neutralizing antibodies to impede gp41 function and to prevent HIV-1 infection. We will bring recent advances from the vaccine side of HIV-1 research into the search for novel therapeutics. When completed, the project will not only yield drug candidates for clinical testing, but should also provide novel reagents for further dissecting molecular mechanisms of HIV-1 entry. We will pursue the following specific aims: 1) We will develop a structure-based platform for optimizing small-molecule fusion inhibitors targeting a hydrophobic pocket of HIV-1 gp41; 2) We will produce potent lead compounds that target the gp41 pocket; 3) We will identify small-molecule fusion inhibitors targeting the MPER of HIV-1 gp41.