A Flexible Approach to Avoid Viral Escape Mutations

避免病毒逃逸突变的灵活方法

基本信息

批准号：
8436187
负责人：
Katherine L Seley-Radtke
金额：
$ 22.15万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE COUNTY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8436187
关键词：
Affinity Amino Acids Antiviral Agents Attention Binding Binding Sites Biological Combined Modality Therapy Cytomegalovirus DNA-Directed DNA Polymerase DNA-Directed RNA Polymerase Disease Drug Delivery Systems Drug Design Drug Targeting Drug resistance Effectiveness Electronics Enzymes Exhibits FDA approved Finding by Cause Guanosine Triphosphate HIV Hepatitis B Virus Hepatitis C virus Highly Active Antiretroviral Therapy Imino Acids Investigation Laboratories Literature Measures Methodology Multi-Drug Resistance Mutate Mutation Nucleosides Nucleotides Outcome Parents Pathway interactions Pharmaceutical Preparations Play Point Mutation Polymerase Protocols documentation RNA-Directed DNA Polymerase Reporting Research Resistance Role Series Side Simplexvirus Students Tenofovir Testing Therapeutic Toxic effect Training Viral Virus Virus Diseases Work analog analytical method combat design drug development fighting flexibility global health improved inhibitor/antagonist innovation insight mutant novel strategies novel therapeutics nucleobase nucleoside analog nucleoside inhibitor resistance mechanism resistance mutation resistant strain scaffold screening tool

项目摘要

DESCRIPTION (provided by applicant): As a result of the extensive use of antiviral drugs, the emergence of mutant viral strains that are resistant to the currently available nucleoside therapeutics has proven to be a critical problem. Using a combination of drugs that target different viral enzymes (termed highly active anti-retroviral therapy or HAART) has helped for some viruses such as HIV, however undesirable side efects and toxicity are often prevalent and reports of multidrug resistance are increasing. Moreover, combination therapies for HBC and HCV remain limited, thus the search for new therapeutics that can overcome resistance mechanisms is urgent. Recently it was reported that Tenofovir, an FDA-approved flexible acyclic nucleotide, and Etravirine, an FDA-approved flexible heterobase analogue, can overcome resistance mutations in the HIV reverse transcriptase binding site. This flexibility allows them to retain their potency against resistant strains since they can adjust conformationally and positionaly to avoid unfavorable steric or electronic interactions and subsequently engage alternate amino acid residues not previously involved in the mechanism of action. These findings are causing a paradigm shift in how medicinal chemists view flexibility in drug design. As a result, exploitation of flexibility in the nucleobase scaffold can be viewed as a powerful tool for developing drugs that can retain their effectiveness against rapidly mutating viral targets. The specific aims for this proposal are to (i) induce flexibility to the nucleobase scaffold of known nucleoside/nucleotide antiviral drugs and (ii) test their activity against four different viral polymerases/reverse transcriptases, as well as their corresponding mutant strains. The results of this preliminary study with these highly innovative flexible nucleoside analogues will provide valuable new information on antiviral drug design targeting polymerase inhibition. In addition, new and improved methodology for nucleoside analogue synthesis will likely be an outcome. As such, the scientific impact of this work goes beyond just global health research, but will also provide valuable training for students, as the synthetic organic and drug delivery methodologies and the information obtained about polymerases will be highly applicable across a broad scope of diseases.

描述（由申请人提供）：由于广泛使用抗病毒药物，突变病毒菌株的出现对当前可用的核苷疗法具有抗性，这已被证明是一个关键问题。使用靶向不同病毒酶（称为高活性抗逆转录病毒疗法或HAART）的药物对某些病毒（例如HIV）有帮助，但是不良的侧面效率和毒性通常很普遍，并且具有多药耐药性的报道正在增加。此外，HBC和HCV的组合疗法仍然有限，因此，紧急寻找可以克服抗药性机制的新疗法。最近有报道称，替诺福韦是FDA批准的柔性无环核苷酸，而埃特拉维林（FDA批准的柔性异酶模拟）可以克服HIV逆转录酶结合位点中的耐药性突变。这种柔韧性使他们能够保持抵抗抗性菌株的效力，因为它们可以在构象和位置上调节以避免不利的空间或电子相互作用，并随后聘请以前不参与作用机理的替代氨基酸残基。这些发现导致药物化学家如何看待药物设计的灵活性的范式转移。结果，可以将核碱基支架柔韧性的剥削视为开发可以保留其有效性的药物的强大工具，以防止快速突变病毒靶标。该建议的具体目的是（i）诱导已知核苷/核苷酸抗病毒药物的核酶支架的柔韧性，（ii）对四种不同的病毒聚合酶/逆转录酶以及相应的突变株测试其活性。这些初步研究的结果对这些高度创新的柔性核苷类似物将提供有关抗病毒药物设计靶向聚合酶抑制的有价值的新信息。此外，核苷类似物合成的新方法和改进的方法可能是一个结果。因此，这项工作的科学影响不仅限于全球健康研究，但还将为学生提供宝贵的培训，因为合成有机和药物输送方法以及有关聚合酶获得的信息将在广泛的疾病范围内高度适用。