Therapeutic D-peptide Inhibitor of HIV entry

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，全世界有3300万感染者，其中包括100多万美国患者。2008年，有270万新感染病例，200万人死于艾滋病。目前的艾滋病毒治疗结合了几种艾滋病毒抑制剂的药物，并大大延长了许多艾滋病毒患者的生命，但严重的副作用和迅速增加的耐药性是令人担忧的重大问题。因此，继续需要开发具有新的作用机制和更强耐药性的艾滋病毒抑制剂。Navigen Pharmaceuticals是一家针对传染病的药物开发公司。利用发现和设计的结合，我们已经确定了一种新型的HIV进入抑制剂（蛋白酶抗性d肽），它针对HIV保守的细胞外进入机制，克服了现有HIV进入抑制剂的局限性（例如，频繁和高剂量，窄宽度，注射部位反应，以及对耐药性的易感）。我们的主要原型（PIE12-trimer）有效抑制来自所有主要亚型HIV的多种菌株，并且非常难以抵抗。我们已经开发了PIE12-trimer的多种变体，以尽量减少给药频率，并选择了两种我们认为更好的。在这项为期一年的资助申请中，Navigen提出(1)开发一种生物分析方法来支持pie12 -三聚体的临床前开发，(2)测量药代动力学（PK）特性，以及(3)对两种最有希望的先导候选药物进行急性、7天和28天的大鼠毒性研究。这些信息将允许Navigen选择理想的PIE12-trimer变体，具有低毒性和PK特性，与每周给药兼容，以推进ind研究并最终进行临床试验。

DESCRIPTION (provided by applicant): HIV/AIDS remains a formidable global epidemic with 33 million infections worldwide, including over 1 million patients in the US. In 2008, there were 2.7 million new infections and 2 million AIDS-related deaths. Current HIV treatment combines drugs from several classes of HIV inhibitors and has dramatically extended the lives of many HIV patients, but serious side effects and rapidly increasing drug resistance are significant concerns. Thus, there is a continuing need to develop HIV inhibitors with new mechanisms of action and more robust resistance profiles. Navigen Pharmaceuticals is a pharmaceutical development company targeting infectious diseases. Using a combination of discovery and design, we have identified a novel type of HIV entry inhibitor (protease-resistant D-peptide) that targets HIV's conserved extracellular entry machinery and overcomes the limitations of existing HIV entry inhibitors (e.g., frequent and high dosing, narrow breadth, injection site reactions, and susceptibility to resistance). Our lead prototype (PIE12-trimer) potently inhibits diverse strains from all major subtypes of HIV and is extraordinarily elusive to resistance. We have developed multiple variants of PIE12-trimer in an effort to minimize dosing frequency and have selected two that we expect to be superior. In this one-year grant application, Navigen proposes to (1) develop a bioanalytical assay to support preclinical development of PIE12-trimer, (2) measure pharmacokinetic (PK) properties, and (3) conduct acute, 7-day, and 28-day rat toxicity studies on the two most promising lead candidates. This information will allow Navigen to select an ideal PIE12-trimer variant with low toxicity and PK properties compatible with weekly dosing for advancement into IND-enabling studies and ultimately clinical trials. PUBLIC HEALTH RELEVANCE: Navigen Pharmaceuticals is developing a potent and novel inhibitor of HIV entry. The goal of this study is to optimize our lead candidate for weekly dosing and low toxicity. If successful, this new inhibitor will improve the health of HIV/AIDS patients by providing them with a safe and highly effective new therapeutic option.