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）：转化研究中心卓越中心的目标是开发被包膜病毒进入的小分子抑制剂，并测试其在动物疾病模型中的功效。潜在的假设是，包裹的病毒进入含有治疗靶标，可以开发出小分子抑制剂，从而阻止受体的参与，膜融合和细胞运输。大多数类别的有执照的抗病毒药会阻止复制周期的细胞内步骤，通常是通过干扰复制所需的病毒编码酶。少数抗病毒剂阻止了包围病毒的进入：maraviroc，一种小分子，通过GP120对人类免疫缺陷病毒1的CCR5共同受体的参与； Enfuvirtide，一种结合HIV1的GP41并干扰融合的合成肽；和阿甘迪丁/rimantidine，它阻断了某些流感菌株的M2离子通道，以防止病毒核糖核蛋白片段释放到细胞中。缺乏合成进入抑制剂与中和经常阻止病毒进入的抗体的自然保护机制形成鲜明对比。该CERTER将推进两种对病毒进入的小分子抑制的一般方法：直接靶向病毒包膜蛋白；以及针对传染性病毒进入的细胞因子的特定靶向。 靶向包膜蛋白的优点是，小分子不需要进入细胞，从而消除了摄取和潜在的出口问题，并且这种抑制剂可能不太可能与细胞蛋白具有不必要的相互作用。靶向细胞蛋白提供 有吸引力的虽然未经证实的可能性可以抑制一个小病毒进入多个病毒 分子。由从事相互依存项目的6名调查人员组成的团队将发现并推进这两个类别的小分子抑制剂。 相关性：黄病毒和丝状病毒都是严重的病原体，具有关键的未满足临床需求。黄病毒，包括登革热病毒，西尼罗河病毒和黄热病病毒，是广泛的节肢动物传播的人类病原体。每年，大约有1亿人被登革热感染。尽管诸如埃博拉病毒和马尔堡病毒之类的丝状病毒并不像Flavivirus一样广泛，但病例死亡率可能接近90％。该计划旨在确定新的候选治疗化合物来解决这些重要的人类病原体。