Improving Absorption and Targeting of Antiviral Drugs

描述（由研究者提供）：随着最近令人不安的事件预示着紧迫感的增加，NIAID有针对性地研究和开发治疗剂，疫苗，佐剂/免疫刺激剂，以及天花和其他病毒性疾病的诊断。在TSRL公司，我们一直在开发一种前体药物策略，以改进抗病毒药物。可以提高批准药物以及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剂的开发，并减少不期望的性质，例如药物毒性、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，并加强其向特定组织的输送，从而提高疗效。本申请的中心假设是，通过设计靶向在人肠中表达的转运蛋白并靶向将前药部分特异性切割成其母体化合物的“活化”酶的前药，可以改善吸收差的药物的口服吸收，并且可以将药物特异性靶向感兴趣的细胞。对于这个项目，我们建议合成各种肽前药的西多福韦和阿托尿苷和测试它们的转运介导的摄取和细胞和血浆水解。我们的目标是确定前药候选人，显示增强载体介导的摄取和/或病毒特异性激活。那些表现出增强的吸收或活化的候选药物将被测试对牛痘和牛痘病毒的抗病毒活性以及在两种人类细胞系中的细胞毒性。此外，将在试验动物中测试显示增强的摄取或活化和抗病毒活性的候选药物的口服生物利用度。该1期SBIR项目的预期结果是开发试验药物的氨基酸前药类似物，其显示出增强的生物利用度和/或靶向活化，因此具有作为治疗痘病毒病的上级口服治疗剂的潜力。此外，该项目的完成将使TSRL能够在未来开发用于治疗各种疾病的前药。

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.