Small molecule inhibitors of enveloped virus entry

有包膜病毒进入的小分子抑制剂

• 批准号: 8810214
• 负责人: Sean PJ Whelan
• 金额: $ 420.45万
• 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/8810214
• 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-1; Human; Influenza A virus; Instruction; 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; gp-120 Antigen; inhibitor/antagonist; neutralizing antibody; pathogen; prevent; programs; receptor; small molecule; synthetic peptide; therapeutic target; trafficking; uptake

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 gp 120 of human immunodeficiency virus-1; enfuvirtide, a synthetic peptide that binds gp41 of HIVI 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.

这个卓越转化研究中心的目标是开发小分子抑制剂