Broad Spectrum Antiviral Nucleoside Phosphonate Analogs

描述：民用生物防御工作组已将天花病毒等正痘DNA病毒确定为潜在的生物恐怖主义威胁，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，在公共卫生方面引起普遍关注，可能出现的新病原体和现有菌株中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突发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具有广泛活性的抗病毒药物的关键靶标。无环核苷膦酸盐（ANP）西多福韦（HPMPC）显示出治疗相关水平的效力对抗广泛的DNA病毒。然而，ANPs及其环状形式（CNPs）作为抗病毒药物的总体有效性受到其固有的缺乏生物利用度的限制，这源于它们的高极性膦酸基团。基于一种新的前药策略，我们已经创建了一种通用的方法来解决ANP和CNP药物缺乏口服生物利用度和低细胞渗透性的问题，该策略现在已经导致了一种有前途的n -烷基酪氨酸酰胺前药平台的开发。该平台的应用使前药表现出明显增强的口服生物利用度，而且对水痘、牛痘和巨细胞病毒等几种DNA病毒的效力也明显高于母体ANP。在本一期SBIR项目中，我们拟利用hmpc、HPMPA、cHPMPC和cHPMPA 4种ANPs和CNPs对该平台进行优化，通过合成一系列20种前药，对5种不同DNA病毒进行SAR测定。前药将进行化合物稳定性、代谢、口服吸收和抗病毒活性测试，以便在项目的II期部分确定临床前开发的主要候选药物。拟议的计划是基于TSRL公司的John Hilfinger博士和南加州大学的Charles McKenna教授之间建立的药物研究伙伴关系，包括阿拉巴马大学伯明翰分校的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.