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）已经将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疗法使用几种抗病毒药物，一种典型的治疗方法需要至少两种药物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方面的困难给在临床环境中实施HAART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病毒包膜糖蛋白介导的病毒与靶细胞膜融合。T20/Enfuvirtide是第一个也是唯一一个获fda批准的融合抑制剂

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.