Development of inhibitors of HIV membrane fusion

HIV膜融合抑制剂的开发

• 批准号: 6640516
• 负责人: GARY FREY
• 金额: $ 4.64万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6640516
• 关键词: HIV envelope protein gp41; X ray crystallography; antiAIDS agent; combinatorial chemistry; drug design /synthesis /production; high throughput technology; inhibitor /antagonist; membrane fusion; postdoctoral investigator; protein binding; virus infection mechanism

It is currently estimated that 36 million people worldwide are infected with HIV (UNAIDS Report 2000). Current therapies for infection use a cocktail of drugs referred to as HAART (Highly Active Antiretroviral Therapy). The cocktail contains a combination of protease and reverse transcriptase inhibitors that are specific for the virus. Despite the increased effectiveness of this treatment, drug resistance and toxicity remain serious issues. It is the goal of this proposal to develop inhibitors of HIV membrane fusion by finding molecules that can bind to the gp41 inner core domain and prevent the conformational change necessary for viral infection. By going after a different target than traditional therapy it is hoped that they may be used to complement them. A two-fold approach using both rational design methods and high throughput screening will be used to discover small molecules that can bind to the inner core of gp41. Structures will be determined using x-ray crystallography so that structure based design methods can be used to enhance binding affinities. Cell-cell fusion assay will be used to determine the ability of the molecules to inhibit membrane fusion.

目前估计全世界有 3600 万人感染艾滋病毒（联合国艾滋病规划署报告 2000）。目前的感染疗法使用称为HAART（高效抗逆转录病毒疗法）的药物混合物。该混合物含有针对该病毒的蛋白酶和逆转录酶抑制剂的组合。尽管这种治疗的有效性有所提高，但耐药性和毒性仍然是严重的问题。该提案的目标是通过寻找能够与 gp41 内核结构域结合并防止病毒感染所需的构象变化的分子来开发 HIV 膜融合抑制剂。通过追求与传统疗法不同的目标，希望它们可以用来补充传统疗法。将使用合理设计方法和高通量筛选的双重方法来发现可以与 gp41 内核结合的小分子。将使用 X 射线晶体学确定结构，以便可以使用基于结构的设计方法来增强结合亲和力。细胞-细胞融合测定将用于确定分子抑制膜融合的能力。