Optimization of HPMPA and CDV Analogs for Treatment of Smallpox

描述(由申请人提供)：本提案的目的是评估治疗天花和疫苗接种并发症的有效新药。天花由天花病毒引起，是一种重要的生物恐怖威胁，尽管有足够的天花疫苗可用，但有许多理由需要FDA批准的、可自行给药的口服活性抗病毒药物。多达4000万人不适合接种疫苗，包括艾滋病、免疫抑制、器官移植、癌症化疗和常见皮肤病患者。暴露后接种疫苗过晚的接触者，可能无法及时获得免疫保护，预防感染和死亡。此外，还描述了可以绕过疫苗的免疫保护的痘病毒的IL-4变种。出于这些原因，预防和治疗天花的口服活性药物将是非常可取的。1999年，我们实验室发现了一种口服活性西多福韦脂酸酯，它在预防和治疗感染后疾病的四种痘病毒病动物模型中显示出良好的活性，该类似物目前正在开发中。开发中出现了一些问题，如果要获得FDA的批准，就必须克服这些问题。这些包括对胃肠道的毒性和关键的猴痘病毒疾病模型的快速降解，根据动物等效性规则，这些都是FDA批准的。最近，我们开发了一种创新的药物化学范式来稳定痘病毒抗病毒药物，如十六烷基氧丙基-西多福韦(CMX001)，以防止在灵长类动物中的快速降解。在这个项目中，我们建议在痘病毒感染的细胞和正痘病毒病的致死动物模型中对这些新药进行深入的评估。我们将开展研究，以评估化学结构对其在猴子肝脏S9组分中的代谢稳定性、胃肠道转运和毒性的影响，并在致死性的牛痘病毒病动物模型上进行测试，包括皮疹、牛痘和牛痘。传统的痘病毒抗病毒药物和新的代谢稳定的类似物将在一项口服猴子药物动力学概念验证研究中进行比较。其中几个新化合物对其他病毒具有广泛的抗病毒活性，包括人类免疫缺陷病毒、疱疹病毒组病毒、乙肝和丙型肝炎病毒和多瘤病毒，并可能在临床上用于除天花之外的其他疾病 我们发现了几种新的抗病毒药物，用于预防和治疗天花，天花是生物恐怖主义的重要威胁因素。在这个项目中，我们将选择最有效的化合物并测试它们在猴子身上的代谢稳定性，这是FDA批准的必要模型，并在致命的痘病毒病动物模型中测试它们的活性。该项目可能导致更安全和更有效的药物，用于天花和民用病毒疾病的生物防御，因为这些药物是广谱抗病毒药物，对许多病毒感染有效。

DESCRIPTION (provided by applicant): The objective of this proposal is to evaluate potent new drugs for smallpox and vaccination complications. Smallpox, caused by the variola virus, is an important bioterrorist threat and although sufficient smallpox vaccine is available, there are a number of reasons to have an FDA approved, orally active antiviral drug which can be self administered. Up to 40 million persons are not good candidates for vaccination including those with AIDS, immunosuppression, organ transplants, cancer chemotherapy and common skin diseases. Exposed persons who are vaccinated too late after exposure may not gain immune protection in time to prevent infection and death. In addition, IL-4 variants of poxviruses have been described which can bypass immune protection of vaccines. For these reasons, an orally active drug for the prevention and treatment of smallpox would be highly desirable. In 1999, our laboratory discovered an orally active lipid ester of cidofovir which shows excellent activity in four animal models of poxvirus disease, both preventing disease and treating disease after infection and this analog is currently in development. Issues have arisen in development which must be overcome if FDA approval is to be obtained. These include toxicity to the GI tract and fast degradation in pivotal monkey models of poxvirus disease which are required for FDA approval under the Animal Equivalence Rule. Recently, we developed a innovative medicinal chemistry paradigm to stabilize poxvirus antivirals like hexadecyloxypropyl-cidofovir (CMX001) against rapid degradation in primates. In this project, we propose in depth evaluation of these new drugs in poxvirus infected cells and in lethal animal models of orthopoxvirus disease. We will carry out studies to evaluate the effects of chemical structure on their metabolic stability in monkey liver S9 fractions, gastrointestinal transit and toxicity and test them in lethal animal models of poxvirus disease including, ectromelia, cowpox and vaccinia. Conventional poxvirus antivirals and the new metabolically stable analogs will be compared in an oral monkey pharmacokinetics proof of concept study. Several of these new compounds have a broad spectrum of antiviral activity against other viruses including the human immunodeficiency virus, herpes group viruses, hepatitis B and C viruses and polyoma virus and may find clinical uses for other diseases in addition to smallpox We have discovered several new antiviral drugs for the prevention and treatment of smallpox, an important threat agent for bioterrorism. In this project, we will select the most effective compounds and test them for metabolic stability in monkeys, the required model for FDA approval, and test their activity in lethal animal models of poxvirus disease. This project could lead to safer and more effective drugs for biodefense against smallpox as well as for civilian viral diseases because the agents are broad spectrum antivirals which are active against many viral infections.