Broad Spectrum Antiviral Nucleoside Phosphonate Analogs

描述：民用生物防御工作组已将天花等正头DNA病毒确定为潜在的生物恐怖主义威胁，以及许多其他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，在公共卫生背景下引起普遍关注，以及可能出现的新病原体和现有菌株产生抗药性的可能性。因此，开发对广泛已知和新出现的病毒病原体有效的新化合物是NIAID的高度优先事项。DNA病毒并不是一成不变的，但它们在生命周期中都有DNA合成的要求。因此，这一基本过程仍然是抗病毒药物具有广泛活性的关键目标。无环核苷膦(ANP)西多福韦(HPMPC)显示出治疗相关水平的效力，对广泛的DNA病毒。然而，ANP及其环形式(CNP)作为抗病毒药物的整体有效性受到了它们固有的生物利用度的限制，这是由于它们的高极性膦酸基引起的。我们创造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，这是基于一种新的前药战略，现在已经导致了一个有前景的N-烷基酪氨酰胺前药平台的开发。这一平台的应用使前药显示出显著的口服生物利用度，但也比母体ANP对几种DNA病毒：水痘、牛痘和CMV的效力要强得多。在这个第一阶段的SBIR项目中，我们建议用4个ANP和CNP来优化这个平台：HPMPC，HPMPA，cHPMPC和cHPMPA，通过合成一系列20种前药来确定与五种不同DNA病毒的SAR。这些前药物将进行化合物稳定性、新陈代谢、口服吸收和抗病毒活性测试，以便在该项目的第二阶段确定临床前开发的主要候选药物。拟议的计划是基于TSRL公司的约翰·希尔芬格博士和南加州大学的查尔斯·麦肯纳教授之间建立的药物研究伙伴关系，并包括阿拉巴马大学伯明翰分校的马克·普里查德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.