Design and Synthesis of HIV Integrase as Potential Anti-AIDS Drugs

HIV整合酶的设计与合成作为潜在的抗艾滋病药物

• 批准号: 9343543
• 负责人: TERRENCE BURKE
• 金额: $ 41.87万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9343543
• 关键词: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Area; Binding; Biochemical; Biological Assay; Clinical; Collaborations; Complementary DNA; DNA; Data; Development; Enzymes; FDA approved; Generations; Genome; HIV; HIV Integrase; HIV Integrase Inhibitors; HIV-1; HIV-1 integrase; Infection; Integrase; Integrase Inhibitors; Ions; Laboratories; Lead; London; Modification; Naphthyridines; Pharmaceutical Preparations; Polymerase; Positioning Attribute; Process; RNA-Directed DNA Polymerase; Reaction; Research Institute; Resistance; Ribonuclease H; Series; Spumavirus; Structural Biologist; Structure; Transferase; Variant; Viral; Virus; Work; anti-viral efficacy; base; cytotoxicity; design; divalent metal; improved; indexing; inhibitor/antagonist; insight; member; mutant; nanomolar; novel therapeutics; prototype; resistant strain; scaffold

Inhibitors of HIV-1 integrase (IN) inhibitors represent the most recent anti-AIDS drugs. Merck's raltegravir (RAL) (October 2007) and Gilead's elvitegravir (EVG) (August 2012) were the first two IN inhibitors to be approved by the FDA. These agents are members of a class of drugs called "IN strand transfer inhibitors" (INSTIs), due to their ability to preferentially block the enzyme's strand transfer (ST) reaction as compared to the enzymes 3'-processing (3'-P) reaction. Treatment with RAL and EVG selects for resistant forms of HIV and there is considerable cross-resistance to these two drugs. GlaxoSmithKline's dolutegravir (DTG) was approved by the FDA in August of 2013 as a 2nd-generation INSTI having improved efficacies against RAL and EVG-resistant strains of HIV. However, DTG also selects for resistant strains of HIV, emphasizing the need for continued development of agents that can overcome resistant strains of IN, including the emerging DTG-resistant strains. Utilizing my laboratory's design and synthetic capabilities, we have teamed with pharmacologists (Dr. Yves Pommier, NCI), virologists (Dr. Hughes, NCI) and structural biologists (Dr. Cherepanov, London Research Institute) to develop new IN inhibitors. These efforts have resulted in the discovery of 1-hydroxy-1,8-naphthyridin-2H-one-3-carboxamides, which potently inhibit wild-type (WT) IN in biochemical assays and show good anti-viral efficacies in single-round infection assays of HIV-1 infectivity. Importantly, members of this series retain good anti-viral potency against RAL-resistant mutants in the latter assays. More recently, we have found by introducing modifications to the 6-position of the 1-hydroxy-2-oxo-1, 8-naphthyridine scaffold, that we are able to obtain INSTIs with low nanomolar potencies against an entire panel of viruses, including the canonical INSTI-resistant IN variants. The compounds are characterized by low cytotoxicities, which in several cases, results in selectivity indices (CC50/EC50) of greater than 10,000. In collaboration with Dr. Cherepanov, we have obtained co-crystal structures of our lead inhibitors bound to the prototype foamy virus (PFV) "intasome" (tetrameric integrase with substrate DNA). This data clarifies the structural basis of the compounds' actions and provides key insights that may be useful in further optimizing biochemical efficacies. Along with IN, the HIV-1 polymerase (Pol) and RNase H domains of reverse transcriptate (RT), belong to a superfamily of polynucleotidyl transferases that share a similar catalytic mechanism involving two divalent metal ions. We have found that members of our recent INSTIs inhibit both the Pol and RNase H activities of RT. Work is in progress to further develop inhibitors directed at these targets.

HIV-1整合酶（IN）抑制剂代表了最新的抗艾滋病药物。默克公司的雷特格韦（RAL）（2007年10月）和吉利德的埃替格韦（EVG）（2012年8月）是FDA批准的前两种IN抑制剂。这些试剂是称为“IN链转移抑制剂”（INSTI）的一类药物的成员，因为与酶3 '-加工（3'-P）反应相比，它们能够优先阻断酶的链转移（ST）反应。用RAL和EVG治疗选择耐药形式的HIV，并且对这两种药物存在相当大的交叉耐药性。GlaxoSmithKline的dolutegravir（DTG）于2013年8月被FDA批准为第二代抗HIV药物，对RAL和EVG耐药株的疗效有所改善。然而，DTG也选择HIV的耐药株，强调需要继续开发能够克服IN耐药株的药物，包括新出现的DTG耐药株。利用我的实验室的设计和合成能力，我们与药理学家（Yves Pompeo博士，NCI），病毒学家（Hughes博士，NCI）和结构生物学家（Cherepanov博士，伦敦研究所）合作开发新的IN抑制剂。这些努力导致发现了1-羟基-1，8-萘啶-2H-酮-3-甲酰胺，其在生物化学测定中有效地抑制野生型（WT）IN，并且在HIV-1感染性的单轮感染测定中显示出良好的抗病毒功效。重要的是，该系列的成员在后一种测定中保留了针对RAL抗性突变体的良好抗病毒效力。最近，我们发现通过对1-羟基-2-氧代-1，8-萘啶支架的6位引入修饰，我们能够获得针对整个病毒组（包括典型的INSTI抗性IN变体）具有低纳摩尔效力的INSTI。这些化合物的特征在于低细胞毒性，在一些情况下，导致选择性指数（CC 50/EC 50）大于10，000。与Cherepanov博士合作，我们已经获得了与原型泡沫病毒（PFV）“intasome”（具有底物DNA的四聚体整合酶）结合的先导抑制剂的共晶体结构。这些数据阐明了化合物作用的结构基础，并提供了可能有助于进一步优化生化功效的关键见解。HIV-1聚合酶（Pol）和逆转录酶（RT）的RNA酶H结构域与IN沿着属于多核苷酸转移酶超家族，它们共享涉及两种二价金属离子的类似催化机制。我们已经发现，我们最近的INSTIs的成员抑制逆转录酶的Pol和RNA酶H的活动。工作正在进行中，以进一步开发针对这些目标的抑制剂。