Therapeutic D-peptide Inhibitor of HIV Entry

HIV 进入的治疗性 D 肽抑制剂

• 批准号: 8467396
• 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 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8467396
• 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; 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; public health relevance; 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）：每年有3,300万人患有艾滋病毒/艾滋病的人（包括在美国的120万人）和180万与艾滋病相关的死亡，艾滋病毒/艾滋病仍然是一种强大的全球流行病（UNAIDS，CDC）。现代艾滋病毒疗法结合了来自不同类别的药物，形成了“鸡尾酒”疗法，这些疗法大大延长了许多艾滋病毒患者的寿命。但是，副作用和耐药性仍然是严重的关注点。因此，具有新的艾滋病毒抑制剂具有新的作用机理和更强的抵抗障碍。 Navigen是一家针对传染病的制药开发公司。通过创新的发现和设计过程，我们确定了一种新型的HIV进入抑制剂（抗蛋白酶的D肽），该抑制剂针对HIV的保守入口机制，并克服了该抑制剂类别的当前局限性。我们的铅候选人（Chol-Pie12-Trimer）以高效力抑制来自所有主要HIV亚型的各种菌株，并具有前所未有的耐药性障碍。此外，从我们的I期SBIR临床前研究中出现了Chol-Pie12-Trimer，具有药代动力学（PK）和物理化学特性，这些特性将支持每周一次，甚至一个月（带有仓库配方）皮下注射一次的发育。 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.这些数据将用于选择最终的候选人来促进IND，并最终作为可销售的入境抑制剂。该提案还将提供有价值的毒理学数据，这些数据将推动D肽作为针对多种病毒感染和其他疾病的治疗平台。