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

针对 HIV-1 g 融合中间态的小分子融合抑制剂

基本信息

批准号：
8901482
负责人：
Bing Chen
金额：
$ 43.96万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8901482
关键词：
Adverse effects Affinity Antigens Antiviral Agents Binding Biological Assay CCR5 gene CD4 Antigens CXCR4 gene Cell membrane Chronic Cleaved cell Clinical Clinical Trials Computer Assisted Crystallography DNA Sequence Rearrangement Drug resistance Effectiveness Event FDA approved Glycoproteins Goals HIV Envelope Protein gp120 HIV-1 Health Highly Active Antiretroviral Therapy Infection Inhibitory Concentration 50 Lead Mediating Membrane Molecular Molecular Conformation Molecular Target N-terminal Oral Patients Peptides Pharmaceutical Preparations Reagent Regimen Research Resistance Resolution Side Specificity Structure Structure-Activity Relationship Surface System T-20 Testing Therapeutic Vaccines Viral Virion Virus base chemical synthesis compliance behavior design drug candidate drug development gp160 high throughput screening improved inhibitor/antagonist neutralizing antibody novel novel therapeutics prevent receptor research clinical testing small molecule tool

项目摘要

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.

描述（由申请人提供）：高效抗逆转录病毒疗法 (HAART) 已将 HIV-1 感染从一度致命的疾病转变为可控制的慢性疾病。最新的HAART方案使用多种类型的抗病毒疗法，并且典型的疗法需要至少两类中的三种或多种药物的组合。耐药性、严重的副作用和治疗依从性困难给HAART在临床上的实施带来了挑战，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病毒包膜糖蛋白介导的病毒与靶细胞膜的融合。 T20/Enfuvirtide是第一个也是唯一一个被批准的融合抑制剂美国食品和药物管理局。肽类药物的局限性以及耐药病毒的迅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的小分子融合抑制剂，以克服基于肽的药物的局限性并增加可用的HAART疗法类别的范围。包膜糖蛋白 gp41 的瞬时构象状态是 HIV-1 融合抑制剂（例如 T-20/Enfuvirtide）（第一个批准的进入抑制抗病毒药物）和某些中和抗体的目标。在这个在该项目中，我们假设 HIV-1 gp41 是一个“可成药”的靶点，我们可以针对该靶点开发小分子融合抑制剂，以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仿基于肽的抗病毒药物或中和抗体来阻碍 gp41 功能并预防 HIV-1 感染。我们将把 HIV-1 研究的疫苗方面的最新进展带入新疗法的探索中。完成后，该项目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型试剂。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口袋的强效先导化合物； 3）我们将鉴定针对HIV-1 gp41的MPER的小分子融合抑制剂。