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Optimizing HIV reverse transcriptase inhibitors through structural, kinetic and cellular approaches

通过结构、动力学和细胞方法优化 HIV 逆转录酶抑制剂

基本信息

批准号：
9378691
负责人：
Albert Hay Wah Chan
金额：
$ 5.71万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9378691
关键词：
Acquired Immunodeficiency Syndrome Active Sites Address Adverse effects Affinity Anti-HIV Agents Antiviral Agents Binding Biological Assay Biology Catechols Cells Combined Modality Therapy Complex Computing Methodologies Crystallization DNA Development Dissociation Docking Drug Design Drug Targeting Drug resistance Enzyme Inhibitor Drugs Enzymes Epidemic Etiology Exhibits FDA approved Free Energy Future Generations Goals HIV HIV therapy HIV-1 Health Highly Active Antiretroviral Therapy Human Individual Kinetics Knowledge Life Expectancy Literature Measures Methods Modeling Molecular Mutation Nucleosides Nucleotides Pathogenesis Pharmaceutical Preparations Pharmacology Polymerase Process Property RNA-Directed DNA Polymerase Research Resistance Resistance development Resistance profile Retroviridae Reverse Transcriptase Inhibitors Safety Series Solubility Structure Structure-Activity Relationship System T-Lymphocyte Testing Tetrazolium Therapeutic Toxic effect Treatment Failure Treatment Protocols Uracil Variant Viral Load result Virus Virus Replication Work X-Ray Crystallography base cytotoxicity design improved inhibitor/antagonist non-nucleoside reverse transcriptase inhibitors novel novel therapeutics public health relevance structural biology synergism transmission process

项目摘要

DESCRIPTION (provided by applicant): Retrovirus HIV, the etiological agent of the global AIDS epidemic, has been a major health concern since its discovery in 1981. Currently, the most successful treatment regimen is the highly active anti-retroviral therapy (HAART), which combines three or four of the current 26 FDA-approved HIV drugs in treatment. Half of these drugs target the reverse transcriptase (RT) enzyme that is essential for viral replication. Among the RT inhibitors, five are non-nucleoside reverse transcriptase inhibitors (NNRTIs) which bind to an allosteric pocket of RT. NNRTIs can inhibit the polymerase function by themselves, or synergistically with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) that bind to the active site of the enzyme. Currently, NNRTIs are always combined with NRTIs in HAART to maximize synergy and efficacy. Although HAART has been successful in extending the life expectancy of HIV-infected individuals, several limitations to this treatment regimen exist, including solubility of individual drug, long-term toxic side effects and drug resistance. Therefore, the long term goal of this research is to develop safer, next generation therapeutics with improved pharmacological properties (PK/PD) and solubility that can overcome resistant variants. Using computational approaches, we have previously developed novel NNRTIs that have very potent antiviral activity (best EC50 = 530 pM) against HIV-1 as well as resistant variants of HIV-1 with common RT mutations. Moreover, our compounds exhibit much lower cytotoxicity and higher solubility than the FDA-approved second generation NNRTIs etravirine and rilpivirine. In order to further develop these compounds into useful therapeutics, binding affinity and association/dissociation rates will be determined using pre-steady state kinetics. Moreover, RT- inhibitor interactions will be elucidated with x-ray crystallography to provide a platform for rational drug design. Furthermore, antiviral activity of novel NNRTIs developed in our lab will be measured using cell-based assays, and changes in potency when combined with current FDA-approved NRTIs will be examined to find the combination that displays the highest synergistic effect. Finally, the molecular mechanism of NRTI-NNRTI synergy will be investigated by solving a quaternary RT:DNA:NRTI:NNRTI structure. Overall, this research will allow us to develop more potent NNRTIs with improved pharmacological properties, and identify the optimal combination of NNRTI and NRTI for combination therapy that should lower treatment failure rate and delay development of resistance.