A Flexible Approach to Avoid Viral Escape Mutations

避免病毒逃逸突变的灵活方法

• 批准号: 8228586
• 负责人: Katherine L Seley-Radtke
• 金额: $ 19.57万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228586
• 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 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; Screening procedure; 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; tool

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. PUBLIC HEALTH RELEVANCE: Recent reports of flexible drugs overcoming resistance to currently used antiviral therapeutics due to their ability to adapt conformationally is gaining attention as a new approach to drug development. This application focuses on the synthesis and antiviral screening for a series of flexible nucleoside analogues that we anticipate will exhibit potency against a number of viruses by not only inhibiting viral polymerases, but also their mutated strains. The impact of this project goes beyond just global health research, but will also provide valuable training for students. Moreover, the information obtained about nucleosides and polymerases from this preliminary study will be highly applicable across a broad scope of viral diseases.

描述（由申请人提供）：由于抗病毒药物的广泛使用，对目前可用的核苷治疗剂具有抗性的突变病毒株的出现已被证明是一个关键问题。使用靶向不同病毒酶的药物组合（称为高效抗逆转录病毒疗法或HAART）对某些病毒（如HIV）有帮助，但不良副作用和毒性通常很普遍，并且多药耐药性的报告正在增加。此外，HBC和HCV的联合治疗仍然有限，因此迫切需要寻找能够克服耐药机制的新疗法。最近，据报道，替诺福韦，FDA批准的柔性无环核苷酸，和依曲韦林，FDA批准的柔性杂碱基类似物，可以克服在HIV逆转录酶结合位点的耐药性突变。这种灵活性使它们能够保留其针对耐药菌株的效力，因为它们可以在构象和位置上进行调整，以避免不利的空间或电子相互作用，并随后接合之前未参与作用机制的替代氨基酸残基。这些发现正在引起药物化学家如何看待药物设计灵活性的范式转变。因此，利用核碱基支架的灵活性可以被视为开发药物的有力工具，这些药物可以保持其对快速突变的病毒靶标的有效性。该提议的具体目的是（i）诱导已知核苷/核苷酸抗病毒药物的核碱基支架的柔性和（ii）测试它们对四种不同病毒聚合酶/逆转录酶以及它们相应的突变株的活性。这些高度创新的灵活核苷类似物的初步研究结果将为靶向聚合酶抑制的抗病毒药物设计提供有价值的新信息。此外，新的和改进的核苷类似物合成方法可能是一个成果。因此，这项工作的科学影响不仅仅是全球健康研究，而且还将为学生提供有价值的培训，因为合成有机和药物输送方法以及获得的有关聚合酶的信息将高度适用于广泛的疾病。 公共卫生相关性：最近报道的柔性药物克服目前使用的抗病毒治疗药物的耐药性，由于他们的能力，以适应构象作为一种新的药物开发方法越来越受到关注。本申请的重点是一系列灵活的核苷类似物的合成和抗病毒筛选，我们预计这些核苷类似物将通过不仅抑制病毒聚合酶，而且抑制其突变株而对许多病毒表现出效力。该项目的影响不仅仅是全球健康研究，还将为学生提供宝贵的培训。此外，从这项初步研究中获得的关于核苷和聚合酶的信息将高度适用于广泛的病毒性疾病。