Broad Spectrum Antiviral Nucleoside Phosphonate Analogs

产品说明：民用生物防御工作组已确定天花等正痘DNA病毒是潜在的生物恐怖主义威胁，而许多其他DNA病毒，包括疱疹病毒、腺病毒、痘病毒、多瘤病毒和乳头瘤病毒，在公共卫生方面受到普遍关注，新病原体的可能出现以及现有菌株产生耐药性的可能性也是如此。因此，开发有效对抗广谱已知和新出现的病毒病原体的新化合物是NIAID的高度优先事项。DNA病毒并不统一，但在其生命周期中都需要DNA合成。因此，这一基本过程仍然是抗病毒药物的关键目标，旨在拥有广泛的活性。无环核苷膦酸酯（ANP）西多福韦（HPMPC）对多种DNA病毒表现出治疗相关水平的效力。然而，ANP及其环状形式（CNP）作为抗病毒剂的整体有用性受到其固有的生物利用度缺乏的限制，这是由其高极性膦酸酯基团引起的。我们已经创建了一种通用方法来解决ANP和CNP药物缺乏口服生物利用度和低细胞渗透性的问题，该方法基于一种新的前药策略，该策略现已导致开发出有前途的N-烷基酪氨酸酰胺前药平台。该平台的应用已经导致前药显示出显著增强的口服生物利用度，但也比母体ANP对几种DNA病毒（水痘、牛痘和CMV）的效力显著更大。在该I期SBIR项目中，我们建议通过合成一系列20种前药来优化该平台，其中包括4种ANP和CNP：HPMPC、HPMPA、cHPMPC和cHPMPA，以确定一组5种不同DNA病毒的SAR。将对前药进行化合物稳定性、代谢、口服吸收和抗病毒活性检测，以确定该项目II期部分临床前开发的主要候选药物。拟议的计划是基于TSRL，Inc.的John Hilfinger博士之间建立的药物研究伙伴关系。和南加州大学的Charles McKenna教授，以及伯明翰的亚拉巴马大学的Mark Prichard教授作为参与的病毒学家。

DESCRIPTION: The Working Group for Civilian Biodefense has identified orthopox DNA viruses such as variola as a potential bioterrorism threat, and numerous other DNA viruses, including herpes, adeno, pox, polyoma and papilloma viruses, are of general concern in a public health context, as are the possible emergence of new pathogens and the potential for development of drug resistance in existing strains. The development of new compounds effective against a broad spectrum of known and emergent viral pathogens is thus a high priority for NIAID. DNA viruses are not uniform but all have a requirement for DNA synthesis during their life cycle. This essential process therefore remains a key target for antiviral drugs intende to possess broad activity. The acyclic nucleoside phosphonate (ANP) cidofovir (HPMPC) exhibits therapeutically relevant levels of potency against a wide range of DNA viruses. However, the overall usefulness of ANPs and their cyclic forms (CNPs) as antiviral agents has been limited by their inherent lack of bioavailability, which arises from their highly polar phosphonate groups. We have created a general approach to address the lack of oral bioavailability and low cellular permeability of ANP and CNP drugs, based on a novel prodrug strategy that has now led to the development of a promising N-alkyl tyrosinamide prodrug platform. Application of this platform has resulted in prodrugs showing markedly enhanced oral bioavailability, but also significantly greater potency than the parent ANP against several DNA viruses: varicella, cowpox and CMV. In this Phase I SBIR project, we propose to optimize this platform with 4 ANPs and CNPs: HPMPC, HPMPA, cHPMPC and cHPMPA, by synthesizing a series of 20 prodrugs to determine SAR with a set of five diverse DNA viruses. The prodrugs will be tested for compound stability, metabolism, oral absorption and antiviral activity in order to identify lead candidates for preclinical development during the Phase II portion of the project. The proposed program is based upon an established drug research partnership between Dr. John Hilfinger at TSRL, Inc. and Professor Charles McKenna at the University of Southern California and includes Professor Mark Prichard at the University of Alabama at Birmingham as the participating virologist.