Mechanistic Approaches to Inhibition of Emerging DNA Viruses

抑制新兴 DNA 病毒的机制方法

基本信息

批准号：
9456556
负责人：
CHARLES E MCKENNA
金额：
$ 25.55万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9456556
关键词：
Address Affect Alabama Amino Acids Anabolism Antibodies Antiviral Agents Biological Assay Biological Availability Biology Bromodeoxyuridine California Cell Culture Techniques Cells Cidofovir Clinic Clinical Collaborations Cytomegalovirus Cytoplasm DNA DNA Viruses Data Detection Development Disease Effectiveness Esters Evaluation Exhibits Family Fibroblasts Foscarnet Future Goals HHV-6B Health Herpesviridae Herpesvirus 1 Human In Vitro Individual Infection Intestines Laboratories Length Liquid substance Liver Measures Metabolic Metabolism Methods Molecular Molecular Probes Molecular Structure Nucleosides Nucleotides Oral Orthopoxvirus Parents Pathogenicity Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phosphate Buffer Phospholipase C Phospholipids Physiological Plasma Polyomavirus Positioning Attribute Prodrugs Property Public Health Rattus Research Research Personnel Research Project Grants Series Solubility Stomach Structure Structure-Activity Relationship Tissues Translations United States National Institutes of Health Universities Vaccinia virus Variant Viral Virus Virus Diseases adenine analog alkyl group analog anti-viral efficacy aqueous cytotoxicity design effective therapy efficacy testing gastricsin improved in vitro activity indexing innovation insight lipophilicity nephrotoxicity novel novel therapeutics pathogen penis foreskin phosphonate professor scaffold tool uptake viral DNA

项目摘要

PROJECT SUMMARY The NIH has identified a group of infective viruses as “emerging” because they are a growing threat to public health. This high priority list includes several DNA viruses. Infections with DNA viruses result in significant disease, but few drugs have been approved for this class of pathogens. Cidofovir (CDV, HPMPC) is an acyclic nucleoside phosphonate (ANP) known to exhibit activity against a spectrum of DNA viruses. However, like other ANPs as a class, CDV has significant drawbacks, including inherent lack of oral bioavailability, relatively low potency and nephrotoxicity. Certain novel N-alkyl tyrosinamide prodrugs of CDV and its adenine analog HPMPA recently designed and synthesized by the PI, Professor Charles McKenna at the University of Southern California (USC) exhibit greatly enhanced in vitro potency against CMV and several other DNA viruses relative to the parent drugs and improved selectivity indices. An important virus-dependent variation in potency, selectivity and efficacy enhancement is observed, which has not been explained mechanistically. In this R21 project, these prodrugs and a series of analogs with modified promoiety structures designed to affect activation by phospholipase C will be evaluated for stability and permeability under physiological conditions and for activity against CMV, HSV1, VACV and two emerging DNA viruses: HHV-6B and BK virus. The research will focus on associating individual promoiety structural features with uptake into infected cells and release of drug into the cytoplasm for uptake into viral DNA for each virus, using novel 5-BrHPMPU prodrug derivatives as probes. This information, correlated with the stability, metabolism and in vitro antiviral efficacy data for the five viruses will provide important insights into the mechanism underlying the exceptional but varied potency of this new class of prodrugs with respect to the viruses investigated, while introducing an innovative molecular tool to determine drug promoiety effectiveness. It is also expected to identify new, highly potent compounds for future development into effective therapies for infections by these viruses.

项目摘要 NIH将一组感染性病毒确定为“新兴”，因为它们对公众越来越威胁健康。这个高优先级列表包括几种DNA病毒。 DNA病毒感染导致显着疾病，但很少有药物被批准为这类病原体。 Cidofovir（CDV，HPMPC）是无环已知磷酸核苷（ANP）对DNA病毒的活性表现出活性。但是，像其他人一样 ANP作为一类，CDV具有明显的缺点，包括继承缺乏口服生物利用度，相对低效力和肾毒性。 CDV的某些新型N-烷基酪氨酸前药及其腺嘌呤模拟HPMPA 最近由PI设计和合成的，南加州大学的Charles McKenna教授（USC）暴露于对CMV和其他几种DNA病毒相对于父母的体外效力非常增强药物和改善的选择性指数。效力，选择性和效率的重要病毒依赖性变化观察到增强，这尚未进行机理上的解释。在这个R21项目中，这些前药以及一系列具有修改的促进结构的类似物，旨在影响磷脂酶C的激活在物理条件下以及对CMV的活性HSV1，对稳定性和渗透性进行评估 VAVV和两个新兴的DNA病毒：HHV-6B和BK病毒。该研究将重点关注个人促进具有吸收感染细胞的结构特征，并将药物释放到细胞质中以摄取使用新型的5-BRHPMPU前药衍生物作为问题进入病毒DNA。此信息，相关随着稳定性，代谢和五种病毒的体外抗病毒效率数据，将提供重要的见解在这一新类别的前提方面的机制中研究了病毒，同时引入了一种创新的分子工具来确定药物促进效力。还期望它将未来发展的新的，高潜在的化合物识别为有效的这些病毒感染的疗法。