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

描述（由申请人提供）：高效抗逆转录病毒疗法（HAART）已将HIV-1感染从一种致命疾病转变为一种可控制的慢性疾病。最新的HAART方案使用几类抗病毒治疗药物，典型的治疗需要至少两类中的三种或更多种药物的组合。耐药性、严重的副作用和治疗依从性的困难给HAART在临床环境中的实施带来了挑战，并表明需要额外的分子靶点。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和靶细胞膜的融合。T20/恩夫韦肽是第一个也是唯一一个被批准的融合抑制剂。 FDA.与肽类药物相关的限制以及耐药病毒的快速出现限制了其长期使用。因此，期望的目标是开发口服可用的小分子融合抑制剂，以克服基于肽的药物的限制并增加可用的HAART治疗剂类别的范围。包膜糖蛋白gp 41的瞬时构象状态被HIV-1融合抑制剂（如T-20/恩夫韦肽-第一个批准的进入抑制抗病毒药物）和某些中和抗体靶向。在这 我们假设HIV-1 gp 41是一个“可药物化”的靶点，我们可以开发小分子融合抑制剂来阻断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肽的抗病毒药物或中和抗体，以阻止gp 41功能并预防HIV-1感染。我们将把HIV-1疫苗研究的最新进展带入新疗法的研究中。该项目完成后，不仅将产生用于临床测试的候选药物，而且还将为进一步剖析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，用于优化靶向HIV-1 gp 41疏水口袋的小分子融合抑制剂; 2）我们将生产靶向gp 41口袋的有效先导化合物; 3）我们将鉴定靶向HIV-1 gp 41 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.