Small molecule inhibitors of enveloped virus entry

有包膜病毒进入的小分子抑制剂

• 批准号: 8641840
• 负责人: Sean PJ Whelan
• 金额: $ 442.23万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641840
• 关键词: Address; Amantadine; Animal Disease Models; Antiviral Agents; Arthropods; Binding; CCR5 gene; Case Fatality Rates; Categories; Cells; Clinical; Dengue; Dengue Virus; Ebola virus; Enzymes; Filovirus; Flavivirus; Frankfurt-Marburg Syndrome Virus; Goals; HIV Envelope Protein gp120; HIV-1; Human; Influenza A virus; Ion Channel; Licensing; Membrane Fusion; Proteins; Research Personnel; Ribonucleoproteins; T-20; Testing; Therapeutic; Translational Research; Viral; Viral Envelope Proteins; Virus; West Nile virus; Work; Yellow fever virus; cellular targeting; env Gene Products; inhibitor/antagonist; neutralizing antibody; pathogen; prevent; programs; receptor; small molecule; synthetic peptide; therapeutic target; trafficking; uptake

DESCRIPTION (provided by applicant): The goal of this Center for Excellence in Translational Research is to develop small molecule inhibitors of enveloped virus entry and test their efficacy in animal models of disease. The underlying hypothesis is that enveloped viral entry is replete with therapeutic targets to which small molecule inhibitors can be developed, blocking receptor engagement, membrane fusion, and cellular trafficking. Most classes of licensed antiviral drugs block intracellular steps of the replication cycle, often through interfering with virally encoded enzymes required for replication. A handful of antiviral agents block enveloped virus entry: maraviroc, a small molecule that blocks engagement of the CCR5 co-receptor by gp120 of human immunodeficiency virus-1; enfuvirtide, a synthetic peptide that binds gp41 of HIV1 and interferes with fusion; and amantadine/rimantidine, which blocks the M2 ion channel of certain strains of influenza A virus to prevent release of the viral ribonucleoprotein segments into the cell. That paucity of synthetic entry inhibitors starkly contrasts with the natural protection mechanism of neutralizing antibodies that frequently block viral entry. This CETR will advance two general approaches to small molecule inhibition of viral entry: direct targeting of viral envelope proteins; and specific targeting of cellular factors requisite for infectious virus entry. Targeting envelope proteins has the advantage that the small molecules do not need to enter cells, thus eliminating uptake and potential export concerns, and such inhibitors may be less likely to have unwanted interactions with cellular proteins. Targeting cellular proteins offers the attractive though unproven possibility to inhibit the entry of multiple viruses with a single small molecule. A team of 6 investigators working on interdependent projects will discover and advance small molecule inhibitors of both categories. RELEVANCE: Both flaviviruses and filoviruses are serious pathogens with critical unmet clinical needs. Flaviviruses, including dengue virus, West Nile virus, and yellow fever virus, are widespread arthropod-transmitted human pathogens. Approximately 100 million people are infected with dengue alone each year. Although the filoviruses such as Ebola virus and Marburg virus are not as widespread as the flaviviruses, case fatality rates can approach 90%. This program seeks to identify new candidate therapeutic compounds to address these important human pathogens.

描述（由申请人提供）：这个卓越转化研究中心的目标是开发包膜病毒进入的小分子抑制剂，并在动物疾病模型中测试其功效。潜在的假设是，包膜病毒进入充满了治疗靶点，小分子抑制剂可以开发，阻断受体结合，膜融合和细胞运输。大多数获得许可的抗病毒药物通常通过干扰复制所需的病毒编码酶来阻断复制周期的细胞内步骤。少数抗病毒药物阻断包膜病毒的进入：马拉维克，一种阻断人类免疫缺陷病毒-1的gp120结合CCR5共受体的小分子；恩富维肽，一种结合hiv病毒的gp41并干扰融合的合成肽；金刚烷胺/金刚烷定，阻断某些甲型流感病毒株的M2离子通道，以防止病毒核糖核蛋白片段释放到细胞中。合成进入抑制剂的缺乏与经常阻断病毒进入的中和抗体的自然保护机制形成鲜明对比。该ctr将推进两种小分子抑制病毒进入的一般方法：直接靶向病毒包膜蛋白；以及传染性病毒进入所需的细胞因子的特异性靶向。