Improving Absorption and Targeting of Antiviral Drugs

描述(由调查人员提供)：随着最近的令人不安的事件预示着紧迫感的增加，NIAID的目标是研究和开发治疗、疫苗、佐剂/免疫刺激剂以及对天花和其他病毒疾病的诊断。在TSRL公司，我们一直在开发一种前药战略，以改进抗病毒药物。能够提高已批准药物和潜在候选药物的口服生物利用度的策略将促进高效抗病毒药物的开发，并减少不良特性，如药物毒性、患者依从性差以及与当前治疗相关的高成本。该项目的长期目标是改善吸收不良药物的口服吸收，并加强它们对特定组织的输送，从而提高疗效。这一应用的中心假设是，通过设计针对在人体肠道表达的转运蛋白的前体药物，并针对将前体药物部分特异性切割到其母体化合物的“激活”酶，可以改善吸收不良药物的口服吸收，并且药物可以特定地针对感兴趣的细胞。在这个项目中，我们建议合成多种西多福韦和氟尿苷的多肽前体药物，并测试它们的转运体介导的摄取以及细胞和血浆的水解性。我们的目标是确定能够增强载体介导的摄取和/或病毒特异性激活的前药候选药物。这些增强摄取或激活的候选药物将在两个人类细胞系中测试对牛痘和牛痘病毒的抗病毒活性以及细胞毒性。此外，显示增强摄取或激活以及抗病毒活性的候选药物将在试验动物身上进行口服生物利用度测试。这一第一阶段SBIR项目的预期结果是开发试验药物的氨基酸前体药物类似物，这些药物显示出增强的生物利用度和/或定向激活，因此有可能成为治疗痘病毒疾病的优秀口服治疗剂。此外，该项目的完成将使TSRL为未来治疗各种疾病的前药开发奠定基础。

DESCRIPTION (provided by investigator): With recent unsettling events foreshadowing an increased sense of urgency, NIAID has targeted research and development of therapeutics, vaccines, adjuvants/immunostimulants, and diagnostics for small pox and other viral diseases. At TSRL, Inc., we have been developing a prodrug strategy for the improvement of antiviral drugs. Strategies that can improve the oral bioavailability of approved drugs as well as potential drug candidates will facilitate the development of highly effective antiviral agents and reduce undesirable properties such as drug toxicity, poor patient compliance, and high costs associated with current therapy. The long-term goal of this project is to improve the oral absorption of poorly absorbed drugs and to enhance their delivery to specific tissues, thus improving efficacy. The central hypothesis of this application is that oral absorption of poorly absorbed drugs can be improved and drugs can be specifically targeted to the cells of interest by designing prodrugs targeted to transporters expressed in human intestine and targeted to "activation" enzymes that specifically cleave the prodrug moiety to its parent compound. For this project, we propose to synthesize a variety of peptide prodrugs of the cidofovir and floxuridine and test them for transporter-mediated uptake and cellular and plasma hydrolysis. Our goal is to identify prodrug candidates that show enhanced carrier-mediated uptake and/or viral-specific activation. Those candidate drugs showing enhanced uptake or activation will be tested for antiviral activity against vaccinia and cowpox viruses as well as for cytotoxicity in two human cell lines. Further, candidate drugs showing enhanced uptake or activation and antiviral activity will be tested for oral bioavailability in test animals. The expected outcome of this Phase 1 SBIR project is the development of amino acid prodrug analogs of the test drugs that show enhanced bioavailability and/or targeted activation and therefore have potential as superior oral therapeutic agents for treatment of pox virus disease. Further, completion of the project will position TSRL for future prodrug development for treatment of a wide variety of disease states.