Therapeutic D-peptide Inhibitor of HIV Entry

描述（由申请人提供）：有3300万人感染艾滋病毒/艾滋病（包括美国的120万人），每年有180万人死于艾滋病相关疾病，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）。现代艾滋病治疗将不同类别的药物结合起来，形成“鸡尾酒”疗法，大大延长了许多艾滋病患者的生命。然而，副作用和耐药性仍然是严重的问题。因此，人们对具有新作用机制和更强耐药性屏障的新型艾滋病毒抑制剂的需求持续存在。 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，我们已经确定了一种新的HIV进入抑制剂（抗蛋白酶D肽），它靶向HIV的保守进入机制，并克服了目前这种抑制剂的局限性。我们的主要候选人（chol-PIE 12-trimer）以高效力抑制来自所有主要HIV亚型的不同菌株，并具有前所未有的耐药性屏障。此外，chol-PIE 12-三聚体从我们的I期SBIR临床前研究中显示具有药代动力学（PK）和物理化学性质，其将支持每周一次和可能每月一次（具有储库制剂）皮下注射剂的开发。在这项为期三年的资助申请中，我们提出了以下具体目标，以推进chol-PIE 12-trimer向IND申请，并继续探索潜在的备份候选人，包括PIE 12-trimer，如果chol-PIE 12-trimer出现问题：（1）推进chol-PIE 12-三聚体的制备和配制，（2）研究chol-PIE 12-三聚体的ADME性质，（3）与FDA举行IND前会议以讨论我们的非临床和早期临床计划，（4）评估chol-PIE 12-三聚体在标准非人灵长类（NHP）HIV感染模型中的体内概念验证功效，和（5）进一步表征chol-PIE 12-三聚体在大鼠和NHP的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进入IND的最终候选药物，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，将推动D-肽作为对抗各种病毒感染和其他疾病的治疗平台。

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.