Broad Spectrum Antiviral Nucleoside Phosphonate Analogs

广谱抗病毒核苷磷酸盐类似物

• 批准号: 8455647
• 负责人: John M Hilfinger
• 金额: $ 30万
• 依托单位: TSRL, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8455647
• 关键词: 9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine; Address; Adenoviruses; Alabama; Amides; Antiviral Agents; Biological; Biological Availability; Bioterrorism; California; Categories; Cell Culture Techniques; Cell Membrane Permeability; Chickenpox; Cidofovir; Clinic; Cowpox; Cytomegalovirus; DNA Viruses; DNA biosynthesis; Data; Development; Drug Kinetics; Drug resistance; Drug usage; Evaluation; Exhibits; Goals; Hepatic; Herpesviridae; In Vitro; Intestines; Lead; Life Cycle Stages; Metabolism; Modification; National Institute of Allergy and Infectious Disease; Nucleosides; Nucleotides; Oral; Papillomavirus; Parents; Permeability; Pharmaceutical Preparations; Phase; Physiological; Plasma; Polyomavirus; Population; Poxviridae; Process; Prodrugs; Property; Public Health; Research; Research Personnel; Resistance; Series; Small Business Innovation Research Grant; Smallpox; Solubility; Solutions; Technology; Testing; Therapeutic; Tyrosine; Universities; Vaccinia virus; Viral; absorption; analog; base; biodefense; candidate selection; cyclic-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine; cytotoxicity; design; drug candidate; flexibility; improved; in vitro activity; lead series; member; novel; pathogen; phosphonate; pre-clinical; preclinical efficacy; professor; programs; public health relevance; research clinical testing; response; scaffold; working group

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.

描述：民用生物防御工作组已将天花等正痘 DNA 病毒确定为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，在公共卫生领域受到普遍关注。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 的首要任务。 DNA 病毒并不统一，但在其生命周期中都需要 DNA 合成。因此，这一重要过程仍然是具有广泛活性的抗病毒药物的关键目标。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) 作为抗病毒药物的整体用途受到其固有的生物利用度缺乏的限制，这是由于其高极性膦酸酯基团造成的。基于一种新颖的前药策略，我们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，该策略现已导致开发出有前景的 N-烷基酪氨酸酰胺前药平台。该平台的应用使得前药的口服生物利用度显着增强，而且对抗多种 DNA 病毒（水痘、牛痘和巨细胞病毒）的效力也比母体 ANP 显着增强。在这个 I 期 SBIR 项目中，我们建议使用 4 种 ANP 和 CNP：HMPPC、HMPPA、cHPMPC 和 cHMPPA 来优化该平台，通过合成一系列 20 种前药来确定一组五种不同 DNA 病毒的 SAR。将测试这些前药的化合物稳定性、代谢、口服吸收和抗病毒活性，以便确定该项目第二阶段临床前开发的主要候选药物。拟议的计划基于 TSRL, Inc. 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合作伙伴关系，其中参与的病毒学家包括阿拉巴马大学伯明翰分校的 Mark Prichard 教授。