Novel therapeutics targeting the membrane proximal external region of HIV-1 Env

针对 HIV-1 包膜近膜外部区域的新型疗法

• 批准号: 9513722
• 负责人: Bing Chen
• 金额: $ 67.38万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-19 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9513722
• 关键词: Adverse effects; Antibodies; Antigens; Antiviral Agents; Binding; Binding Sites; Biological Assay; CCR5 gene; CXCR4 gene; Cell fusion; Cell membrane; Cells; Chronic; Cleaved cell; Clinical; Complex; Drug resistance; Effectiveness; Effector Cell; Epitopes; Event; Exhibits; FDA approved; Fc Receptor; Glycoproteins; Goals; HIV Envelope Protein gp120; HIV-1; Immune; Immunology; Infection; Lead; Libraries; Mediating; Membrane; Membrane Fusion; Membrane Potentials; Molecular; Molecular Conformation; Molecular Mechanisms of Action; Molecular Target; N-terminal; Patients; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Preclinical Testing; Protein Biochemistry; Proviruses; Reagent; Regimen; Research; Resolution; SIV; Side; Structure; Structure-Activity Relationship; Surface; T-20; Testing; Therapeutic; Therapeutic antibodies; Vaccines; Viral; Virion; Virus Inhibitors; X-Ray Crystallography; antiretroviral therapy; base; compliance behavior; design; gp160; high throughput screening; improved; inhibitor/antagonist; killings; neutralizing antibody; new therapeutic target; novel; novel therapeutics; receptor; screening; small molecule; structural biology; therapeutic candidate; therapeutic target; transmission process; virology

Project Summary Combination antiretroviral therapy (cART) has transformed HIV-1 infection, once a fatal illness, to a manageable chronic condition. The latest cART 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 cART 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 (Env). Enfuvirtide is the first and still the only fusion inhibitor approved by FDA, but its limitations have restricted its long-term use. Moreover, the current therapies are not curative since they cannot eliminate latent HIV-1 reservoirs harboring integrated proviruses. Antibody-based therapeutics that can potently inhibit HIV-1 entry and also facilitate killing of Env-expressing cells are promising candidates for reservoir-eliminating strategies. The membrane proximal external region (MPER) of HIV-1 Env is a particularly attractive target for fusion inhibitors because it is one of the most conserved and functionally critical regions of the entire HIV-1 Env. Moreover, we have identified several MPER-directed hit compounds that can specifically inhibit membrane fusion mediated by HIV-1 Env but not SIV Env. Furthermore, the MPER-specific bnAbs exhibit extraordinary breadth in blocking HIV-1 infection and they are excellent candidates for developing therapeutic antibodies. In this project, we hypothesize that the MPER of HIV-1 Env is a promising therapeutic target for developing small-molecule and antibody-based inhibitors of viral membrane fusion. We will bring recent advances from the vaccine side of HIV-1 research into the search for novel therapeutics. We will purse the following specific aims: 1) we will identify small-molecule fusion inhibitors targeting the MPER of HIV-1 Env; 2) we will optimize small-molecule fusion inhibitors targeting the MPER; 3) we will develop antibody-based therapeutics targeting the MPER. When the project is completed, it will not only yield leads for preclinical testing, but should also provide novel reagents for further dissecting molecular mechanisms of HIV-1 entry.

项目摘要 联合抗逆转录病毒疗法（cART）已将HIV-1感染从曾经的致命疾病转变为 可控制的慢性病最新的cART方案使用几类抗病毒治疗药物和一种抗病毒药物。 典型的治疗需要来自至少两类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实施 cART在临床环境中的应用，并表明需要额外的分子靶点。HIV-1的第一个关键步骤 感染是由病毒包膜糖蛋白（Env）介导的病毒和靶细胞膜的融合。恩夫韦肽 是FDA批准的第一个也是唯一一个融合抑制剂，但其局限性限制了其长期应用， 使用.此外，目前的疗法不能治愈，因为它们不能消除潜伏的HIV-1储存库 携带整合的前病毒。基于抗体的治疗剂可以有效地抑制HIV-1进入， 促进对表达Env的细胞的杀伤是消除病毒策略的有希望的候选者。的 HIV-1 Env的膜近端外部区域（MPER）是融合抑制剂的特别有吸引力的靶点 因为它是整个HIV-1 Env中最保守和功能最关键的区域之一。而且我们 已经鉴定了几种能够特异性抑制膜融合介导的MPR定向命中化合物， HIV-1 Env，而不是SIV Env。此外，MPR特异性bnAb在阻断中表现出非凡的宽度， HIV-1感染，它们是开发治疗性抗体的极好候选者。本课题 假设HIV-1 Env的MPER是开发小分子和 基于抗体的病毒膜融合抑制剂。我们将带来疫苗方面的最新进展， HIV-1研究进入寻找新的治疗方法。我们将追求以下具体目标：1）我们将 鉴定靶向HIV-1 Env的MPER的小分子融合抑制剂; 2）我们将优化小分子 靶向MPER的融合抑制剂; 3）我们将开发靶向MPER的基于抗体的治疗剂。 当该项目完成后，它不仅会产生临床前测试的线索，而且还应该提供新的 用于进一步剖析HIV-1进入的分子机制的试剂。