A Flexible Approach to Avoid Viral Escape Mutations

描述(申请人提供)：由于抗病毒药物的广泛使用，对现有核苷疗法产生抗药性的突变病毒株的出现已被证明是一个严重的问题。使用针对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(如艾滋病毒)有帮助，但不良副作用和毒性往往普遍存在，多药耐药的报告也在增加。此外，针对乙肝和丙型肝炎的联合疗法仍然有限，因此迫切需要寻找能够克服耐药机制的新疗法。最近有报道称，FDA批准的柔性非环核苷酸替诺福韦和FDA批准的柔性杂酶类似物依曲韦林可以克服HIV逆转录酶结合位点的耐药突变。这种灵活性使它们能够保持对耐药菌株的效力，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，并随后与以前没有参与作用机制的替代氨基酸残基结合。这些发现正在导致药物化学家对药物设计灵活性的看法发生范式转变。因此，利用核酸基支架中的灵活性可以被视为开发能够保持对快速突变的病毒靶点的有效性的药物的有力工具。这项建议的具体目的是(I)诱导已知核苷/核苷酸抗病毒药物的碱基支架的灵活性，以及(Ii)测试它们对四种不同病毒聚合酶/逆转录酶及其相应突变株的活性。这些高度创新的柔性核苷类似物的初步研究结果将为针对聚合酶抑制的抗病毒药物设计提供有价值的新信息。此外，核苷类似物合成的新的和改进的方法可能会是一个结果。因此，这项工作的科学影响不仅限于全球卫生研究，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获得的关于聚合酶的信息将高度适用于广泛的疾病范围。

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.