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

• 批准号: 7496198
• 负责人: William Ho
• 金额: $ 4.68万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 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/7496198
• 关键词: Acquired Immunodeficiency Syndrome; Active Sites; Affect; African American; Agreement; Binding; Biochemical; Biological Assay; Biological Models; Calorimetry; Cells; Chemicals; Class; Clinic; Collection; Complex; Coupled; Crystallization; Crystallography; DNA; DNA-Directed RNA Polymerase; Data; Deoxyribose; Development; Diagnosis; Disadvantaged; Disruption; Drug Binding Site; Drug Delivery Systems; Drug Design; Drug resistance; Endopeptidases; 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; Numbers; Organelles; Organism; Oxidative Phosphorylation; Peptide Hydrolases; Pharmaceutical Preparations; Polymerase; Population; Process; Production; Property; Proteins; Proteolysis; Public Health; Publishing; RNA; RNA-Directed DNA Polymerase; Range; 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; 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; scaffold; small molecule; therapeutic target

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）：生物体依靠大型分子机器将核酸在脱氧核糖和核糖形式之间转换来传递遗传信息。该提案旨在从人类疾病的角度研究这些分子机器。对于 HIV，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，是病毒复制所必需的。 RT 是一个经过验证的药物靶点，大量通过抑制 RT 发挥作用的疗法就证明了这一点。 RT 上现有药物结合位点的突变导致耐药性，这是化疗干预失败的最大原因，迫使人们开发出能够在面对这些突变时发挥作用的新药物。尽管 RT 的正确功能需要 RH 结构域的活性，但 RT 的核糖核酸酶 H (RNH) 结构域代表了一个未充分利用的药物靶点。此外，RNH 结构域远离当前的药物结合位点，降低了与当前疗法交叉耐药的风险。这项研究将执行多层次策略来发现和开发针对 RT 的新型抑制剂。首先，基于片段的筛选与 X 射线晶体学相结合，将用作筛选化学空间中结合 RNH 活性位点并破坏活性的小分子支架的平台。从片段筛选中获得的信息将用于开发新型 RNH 抑制剂，最终将转化为治疗艾滋病的疗法。其次，将使用 X 射线晶体学来确定与 RT 复合的现有一类 RNH 功能的 N-酰基腙抑制剂的结构。从这些结构中获得的信息将用于阐明下一代更有效的抑制剂的设计。最后，现有类别的 RT 聚合酶活性烯基二芳基甲烷 (ADAM) 抑制剂的相互作用将使用 X 射线晶体学来确定。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 ADAM 类似物的开发，使其在面对耐药突变时仍能保持活性。 公共健康相关性：将通过结构方法发现和开发抑制绝对必需的 HIV 酶功能的新型分子。这些新的抑制剂将有助于对抗艾滋病毒耐药菌株的出现。