New broad-spectrum antivirals: target bunyaviruses

新型广谱抗病毒药物：针对布尼亚病毒

• 批准号: 6690428
• 负责人: PATRICIA L MARION
• 金额: $ 49.67万
• 依托单位: HEPADNAVIRUS TESTING, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6690428
• 关键词: Bunyaviridae; HMG coA reductases; alkyltransferase; antiviral agents; bioterrorism /chemical warfare; combination chemotherapy; dengue; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; genetically modified animals; hepatitis D virus; inhibitor /antagonist; laboratory mouse; mass spectrometry; posttranslational modifications; southern blotting; tissue /cell culture

DESCRIPTION (provided by investigator): Our long-term objectives are to further develop and exploit a new class of antiviral agents with "broadspectrum" activity. In addition to a variety of medically important viruses, the list of targeted viruses includes several NIAID Categories A and B viruses making these compounds valuable potential drugs for this nation's biodefense. The first successful prototype viral target for this novel antiviral strategy was human hepatitis D virus (HDV). This application now seeks to leverage the expertise and reagents available with HDV to begin to expand the therapeutic spectrum of this novel antiviral strategy to combat bunyaviruses. Prenylation, a type of sequence-specific post-translational modification of proteins involves the covalent addition of a prenyl lipid to a sequence motif, termed a "CXXX box." A wide variety of viruses also encode CXXX box-containing proteins, and like HDV are suspected of using prenylation in key aspects of their life cycles, indicating they are prime targets for prenylation inhibition-based antiviral therapy. Excitingly, prenylation inhibitors are surprisingly well tolerated in vivo. We propose to first synthesize sufficient quantities of proven as well as novel agents with prenylation-inhibiting activity, and to then use these compounds in the HDV prototype model to evaluate a novel regimen designed to increase the antiviral potency of prenylation inhibitors. Next we will better characterize the prenylation status of a selected bunyavirus substrate that produces a Dengue-like illness for which no effective therapy exists to date. Finally we will evaluate the latter's sensitivity to the optimized anti-prenylation regimen. Our specific aims are to: 1) synthesize known and improved prenylation inhibitors; 2) determine the synergy potential of combination therapy with HMG-CoA reductase and prenylation inhibitors; 3) characterize the prenylation efficiency and specificity of the absolutely conserved CXXX box-containing protein in a bunyavirus; 4) evaluate the optimized antiprenylation regimen determined from the above aims against a specific bunyavirus target. Together with our collaborators, using our expertise in peptidomimetic design of prenyltransferase inhibitors, molecular virology, and recently developed in vitro and in vivo models for testing prenylation inhibition-based antiviral therapies, we anticipate that successful accomplishment of our aims will yield an invaluable weapon for this nation's biodefense arsenal.

描述（由研究者提供）：我们的长期目标是进一步开发和利用具有“广谱”活性的新型抗病毒药物。除了多种医学上重要的病毒外，目标病毒列表还包括几种 NIAID A 类和 B 类病毒，使这些化合物成为国家生物防御的宝贵潜在药物。这种新型抗病毒策略的第一个成功的原型病毒靶点是人类丁型肝炎病毒（HDV）。该应用现在寻求利用 HDV 可用的专业知识和试剂来开始扩大这种新型抗病毒策略的治疗范围，以对抗布尼亚病毒。异戊二烯化是蛋白质的一种序列特异性翻译后修饰，涉及将异戊烯基脂质共价添加到序列基序上，称为“CXXX 盒”。多种病毒也编码含有 CXXX 盒的蛋白质，并且像 HDV 一样，怀疑在其生命周期的关键方面使用异戊二烯化，这表明它们是基于异戊二烯化抑制的抗病毒治疗的主要目标。令人兴奋的是，异戊二烯化抑制剂在体内具有令人惊讶的良好耐受性。我们建议首先合成足够数量的经过验证的以及具有异戊二烯化抑制活性的新型药物，然后在 HDV 原型模型中使用这些化合物来评估旨在提高异戊二烯化抑制剂的抗病毒效力的新方案。接下来，我们将更好地表征选定的布尼亚病毒底物的异戊二烯化状态，该底物会产生类似登革热的疾病，迄今为止尚无有效的治疗方法。最后我们将评估后者对优化的抗异戊二烯化方案的敏感性。我们的具体目标是：1）合成已知的和改进的异戊二烯化抑制剂； 2) 确定HMG-CoA还原酶和异戊二烯化抑制剂联合治疗的协同潜力； 3) 表征布尼亚病毒中绝对保守的含有CXXX盒的蛋白质的异戊二烯化效率和特异性； 4) 针对特定布尼亚病毒靶标评估根据上述目标确定的优化抗异戊二烯化方案。与我们的合作者一起，利用我们在异戊烯基转移酶抑制剂的拟肽设计、分子病毒学以及最近开发的用于测试基于异戊二烯化抑制的抗病毒疗法的体外和体内模型方面的专业知识，我们预计，我们目标的成功实现将为以下领域带来宝贵的武器：这个国家的生物防御武器库。