Discovery of novel molecular scaffolds that inhibit HIV reverse transcriptase

发现抑制HIV逆转录酶的新型分子支架

基本信息

批准号：
7667931
负责人：
William Ho
金额：
$ 5.01万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7667931
关键词：
Acquired Immunodeficiency Syndrome Active Sites Affect African American Agreement Binding Biochemical Biological Assay Biological Models Calorimetry Cells Chemicals Clinic Collection Complex Coupled Crystallization Crystallography DNA DNA-Directed RNA Polymerase Data Deoxyribose Development Diagnosis Disadvantaged Drug Binding Site Drug Delivery Systems Drug Design Drug resistance Engineering Enzymes Face Failure Generations Genes Genetic Genetic Transcription Genome Genomics HIV HIV-1 Reverse Transcriptase Health Hispanics Histidine Human Hydrazones Individual Intervention Joints Length Libraries Life Life Cycle Stages Ligands Link Location Maps Mass Spectrum Analysis Methods Minority Mitochondria Mitochondrial RNA Molecular Molecular Machines Mutation N-terminal Names Nucleic Acids Organelles Organism Oxidative Phosphorylation Peptide Hydrolases Pharmaceutical Preparations Polymerase Population Process Production Property Proteins Proteolysis Publishing RNA RNA-Directed DNA Polymerase Reaction Resistance Resolution Reverse Transcriptase Inhibitors Ribonuclease H Ribose Risk Saccharomyces cerevisiae Screening procedure Series Structure Testing Therapeutic Therapeutic Intervention Titrations United Nations United States Vendor Viral Virus X-Ray Crystallography analog base cofactor combat design disease phenotype domain mapping drug development human disease inhibitor/antagonist insight melting milligram mitochondrial genome next generation non-nucleoside reverse transcriptase inhibitors novel prevent programs promoter public health relevance resistance mutation resistant strain scaffold small molecule therapeutic target

Acquired Immunodeficiency Syndrome Active Sites Affect African American Agreement Binding Biochemical Biological Assay Biological Models Calorimetry Cells Chemicals Clinic Collection Complex Coupled Crystallization Crystallography DNA DNA-Directed RNA Polymerase Data Deoxyribose Development Diagnosis Disadvantaged Drug Binding Site Drug Delivery Systems Drug Design Drug resistance Engineering Enzymes Face Failure Generations Genes Genetic Genetic Transcription Genome Genomics HIV HIV-1 Reverse Transcriptase Health Hispanics Histidine Human Hydrazones Individual Intervention Joints Length Libraries Life Life Cycle Stages Ligands Link Location Maps Mass Spectrum Analysis Methods Minority Mitochondria Mitochondrial RNA Molecular Molecular Machines Mutation N-terminal Names Nucleic Acids Organelles Organism Oxidative Phosphorylation Peptide Hydrolases Pharmaceutical Preparations Polymerase Population Process Production Property Proteins Proteolysis Publishing RNA RNA-Directed DNA Polymerase Reaction Resistance Resolution Reverse Transcriptase Inhibitors Ribonuclease H Ribose Risk Saccharomyces cerevisiae Screening procedure Series Structure Testing Therapeutic Therapeutic Intervention Titrations United Nations United States Vendor Viral Virus X-Ray Crystallography analog base cofactor combat design disease phenotype domain mapping drug development human disease inhibitor/antagonist insight melting milligram mitochondrial genome next generation non-nucleoside reverse transcriptase inhibitors novel prevent programs promoter public health relevance resistance mutation resistant strain scaffold small molecule therapeutic target

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项目摘要

DESCRIPTION (provided by applicant): Organisms rely on large molecular machines that convert nucleic acids between their deoxyribose and ribose'forms to transmit genetic information. This proposal aims to study these molecular machines from the standpoint of human disease. In the case of HIV, reverse transcriptase (:RT) is responsible for catalyzing the transfer of information from viral genomic RNA to DMA. This series of reactions are crucial steps, and are absolutely required for viral replication. RT is a proven drug target, as evidenced by the number of therapeutics that function by inhibiting RT. Mutations to current drug binding sites on RT which confer resistance is the greatest cause of failure for chemotherapeutic intervention, compelling the development of novel drugs which can function in the face of these mutations. The ribonuclease H (RNH) domain of RT represents an underutilized drug target despite the required activity of the RH domain for proper RT function. Furthermore, the RNH domain is located away from current drug binding sites, reducing the risk of cross-resistance with current therapies. This study will execute a multi-tiered strategy to discover and develop novel inhibitors that target RT. First, fragment based screening in conjunction with x-ray crystallography will be used as a platform for screening chemical space for small molecule scaffolds that bind in the RNH active site and disrupt activity. Information derived from fragment screening will be exploited to develop novel RNH inhibitors that will eventually be turned into therapeutics to treat AIDS. Second, the structures of an existing class of N-acyl hydrazone inhibitors of RNH function in complex with RT will be determined using x-ray crystallography. Information gained from these structures will be used to elucidate the design of the next generation of more potent inhibitors. Finally, the interactions of the existing class of alkenyldiarylmethane (ADAM) inhibitors of RT polymerase activity will be determined using x-ray crystallography. Although effective polymerase inhibitors already exist, this structural information will aid in the development of ADAM analogues that can retain activity in the face of resistance mutations. PUBLIC HEALTH RELEVANCE: Novel molecules that inhibit the function of an absolutely required HIV enzyme will be discovered and developed via structural methods. These new inhibitors will contribute to combating the emergence of drug resistant strains of HIV.

描述（由申请人提供）：生物依赖于大分子机器，这些机器在其脱氧核糖核酸和核糖形式之间转化核酸以传递遗传信息。该建议旨在从人类疾病的角度研究这些分子机器。在HIV的情况下，逆转录酶（：RT）负责催化信息从病毒基因组RNA转移到DMA。这一系列反应是至关重要的步骤，绝对是病毒复制所必需的。 RT是一个被证明的药物靶标，可以通过抑制RT功能的治疗剂数量证明。对RT的当前药物结合位点的突变是赋予耐药性的最大原因是化学治疗干预的最大原因，迫使新型药物的发展，这些药物在面对这些突变时可以起作用。 RT的核糖核酸酶H（RNH）结构域代表了未充分利用的药物靶标，尽管RH结构域需要进行适当的RT功能。此外，RNH结构域远离当前的药物结合位点，降低了与当前疗法的交叉抗性风险。这项研究将执行一种多层策略，以发现和开发针对RT的新型抑制剂。首先，与X射线晶体学结合结合的基于碎片的筛选将用作筛选在RNH活性位点结合并破坏活性的小分子支架的化学空间的平台。将利用从碎片筛选中得出的信息来开发新型的RNH抑制剂，这些抑制剂最终将变成治疗艾滋病的治疗剂。其次，将使用X射线晶体学确定现有的RNH功能N-acyl肼抑制剂的结构。从这些结构中获得的信息将用于阐明下一代更多有效抑制剂的设计。最后，将使用X射线晶体学确定现有类别的RT聚合酶活性的烷烯基甲烷（ADAM）抑制剂的相互作用。尽管有效的聚合酶抑制剂已经存在，但这种结构信息将有助于发展ADAM类似物，这些Adam类似物可以在抗性突变时保持活性。公共卫生相关性：将通过结构方法发现和开发抑制绝对需要HIV酶功能的新分子。这些新的抑制剂将有助于打击艾滋病毒抗药性菌株的出现。