Therapeutic D-peptide Inhibitor of HIV Entry

HIV 进入的治疗性 D 肽抑制剂

• 批准号: 8764703
• 负责人: ALAN L MUELLER
• 金额: $ 100万
• 依托单位: NAVIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-12 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8764703
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adverse effects; Animal Model; Applications Grants; Autopsy; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemistry; Clinic; Clinical; Clinical Research; Clinical Trials; Communicable Diseases; Cytochrome P450; Data; Development; Disease; Dose; Drug Exposure; Drug Formulations; Drug Kinetics; Drug resistance; Ensure; Enzymes; Epidemic; Evaluation; Excretory function; FDA approved; Feces; Future; Fuzeon; Goals; HIV; HIV Entry Inhibitors; HIV Infections; HIV therapy; Health; Human; Infection; Injectable; Investigation; Lead; Life; Liver Microsomes; Metabolism; Methods; Modeling; Mus; Nature; Oryctolagus cuniculus; Parents; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Plasma Proteins; Predisposition; Process; Production; Program Development; Property; Protein Binding; Rattus; Research Design; Resistance; Rodent; Safety; Small Business Innovation Research Grant; Therapeutic; Toxic effect; Toxicokinetics; Toxicology; Urine; Virus Diseases; Work; absorption; analytical method; chemical synthesis; design; experience; in vivo; inhibitor/antagonist; innovation; irritation; manufacturing process; meetings; microbicide; monomer; mouse model; nonhuman primate; novel; novel therapeutics; preclinical study; response; subcutaneous

DESCRIPTION (provided by applicant): With 33 million people living with HIV/AIDS (including 1.2 million in the US), and 1.8 million AIDS-related deaths annually, HIV/AIDS remains a formidable global epidemic (UNAIDS, CDC). Modern HIV therapy combines drugs from different classes to form "cocktail" therapies that have significantly prolonged the lives of many HIV patients. However, side effects and drug resistance remain serious concerns. Thus, there is an enduring need for novel HIV inhibitors with new mechanisms of action and stronger barriers to resistance. Navigen is a pharmaceutical development company targeting infectious diseases. Through an innovative discovery and design process, we have identified a novel HIV entry inhibitor (protease-resistant D-peptide) that targets HIV's conserved entry machinery and overcomes the current limitations of this inhibitor class. Our lead candidate (chol-PIE12-trimer) inhibits diverse strains from all major subtypes of HIV with high potency and possesses an unprecedented barrier to resistance. Further, chol-PIE12-trimer appears from our Phase I SBIR preclinical studies to possess pharmacokinetic (PK) and physicochemical properties that would support development of a once-weekly, and perhaps once-monthly (with depot formulation) subcutaneous injectable. In this three-year grant application, we propose the following specific aims to advance chol-PIE12-trimer towards IND filing, as well as continue to explore potential backup candidates including PIE12-trimer, should problems with chol-PIE12-trimer arise: (1) advance the manufacturing and formulation of chol-PIE12-trimer, (2) investigate the ADME properties of chol-PIE12-trimer, (3) hold a pre-IND meeting with the FDA to discuss our nonclinical and early clinical plans, (4) evaluate the in vivo proof-of-concept efficacy of chol-PIE12-trimer in a standard nonhuman primate (NHP) model of HIV infection, and (5) further characterize the safety of chol- PIE12-trimer in toxicology and safety pharmacology studies in rats and NHPs. These data will be used to select a final candidate for advancement to IND and ultimately to the clinic as a marketable entry inhibitor. This proposal will also provide valuable toxicology data that will advance D-peptides as a therapeutic platform against diverse viral infections and other diseases.

描述（由申请人提供）：艾滋病毒/艾滋病仍然是一种可怕的全球流行病（联合国艾滋病规划署、疾病预防控制中心），每年有 3300 万人感染艾滋病毒/艾滋病（其中美国有 120 万人），每年有 180 万人死于艾滋病相关死亡。现代艾滋病毒疗法将不同类别的药物结合起来形成“鸡尾酒”疗法，显着延长了许多艾滋病毒患者的生命。然而，副作用和耐药性仍然是严重问题。因此，对具有新的作用机制和更强的耐药屏障的新型HIV抑制剂存在着持久的需求。 Navigen 是一家针对传染病的药物开发公司。通过创新的发现和设计过程，我们发现了一种新型 HIV 进入抑制剂（蛋白酶抗性 D 肽），它针对 HIV 保守的进入机制，并克服了此类抑制剂目前的局限性。我们的主要候选药物（chol-PIE12-三聚体）可高效抑制所有主要 HIV 亚型的多种菌株，并具有前所未有的耐药屏障。此外，我们的 I 期 SBIR 临床前研究表明，chol-PIE12-三聚体具有药代动力学 (PK) 和理化特性，这将支持开发每周一次、甚至每月一次（采用长效制剂）皮下注射剂。在这项为期三年的资助申请中，我们提出以下具体目标，以推动 chol-PIE12-三聚体向 IND 申请，并在 chol-PIE12-三聚体出现问题时继续探索包括 PIE12-三聚体在内的潜在备用候选药物：(1) 推进 chol-PIE12-三聚体的制造和配方，(2) 研究 chol-PIE12-三聚体的 ADME 特性，(3) 举行 与 FDA 举行 IND 前会议，讨论我们的非临床和早期临床计划，(4) 评估 chol-PIE12-三聚体在 HIV 感染的标准非人灵长类 (NHP) 模型中的体内概念验证功效，以及 (5) 进一步表征 chol-PIE12-三聚体在大鼠和 NHP 毒理学和安全药理学研究中的安全性。这些数据将用于选择最终候选药物，以推进 IND 并最终作为可上市的进入抑制剂进入临床。该提案还将提供有价值的毒理学数据，推动 D 肽作为针对多种病毒感染和其他疾病的治疗平台。