Protease Stable N-Terminally Modified Therapeutic Peptides

蛋白酶稳定的 N 末端修饰的治疗性肽

• 批准号: 10484456
• 负责人: KRISHNA KUMAR
• 金额: $ 36.74万
• 依托单位: VELUM, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10484456
• 关键词: Academia; Acylation; Address; Agonist; Animal Model; Attenuated; Binding; Biological; Biological Markers; Biological Process; Biological Products; Biotechnology; Blood; Blood Circulation; Body Weight decreased; Charge; Chemicals; Chronic; Clinical; Collaborations; Custom; Development; Diabesity; Digestion; Dipeptidyl Peptidases; Disease; Dose; Effectiveness; Enzymes; FDA approved; Future; General Population; Goals; HIV; Half-Life; Hormone secretion; Hormones; Hydrolysis; Injections; Insulin; Investigational Therapies; Laboratories; Length; Libraries; Ligands; Lipodystrophy; Medical; Medicine; Metabolic; Minor; Modification; Molecular; Morbid Obesity; Mus; N-terminal; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Patients; Peptide Hydrolases; Peptide YY; Peptides; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Pituitary Gland; Property; Refractory; Renal clearance function; Resistance; Safety; Scientist; Serine Protease; Serum; Side; Small Business Technology Transfer Research; Somatotropin; Somatotropin-Releasing Hormone; Stream; Structure; Testing; Therapeutic; Tissues; Toxicology; Trypsin; Universities; Work; analog; appendage; bariatric surgery; base; design; design and construction; fibroblast-activating factor; follow-up; glucagon-like peptide 1; hormone analog; in vivo; interdisciplinary collaboration; interest; mimetics; nonalcoholic steatohepatitis; obese patients; peptide analog; peptide drug; peptide hormone; phase 2 study; preclinical development; preclinical evaluation; preservation; prevent; prototype; public health relevance; receptor; side effect; small molecule; tyrosine analog

PROJECT SUMMARY Peptide therapeutics combine high potency and selectivity, and engender fewer side effects than traditional small molecules. This has fueled interest in peptides filling the gap between ‘biologics’ and small molecules, as peptide-based compounds have key desired properties that are distinct both of the other classes. A major challenge remains to extend the short half-life of native peptides, which are susceptible to rapid enzyme catalyzed hydrolytic cleavage and inactivation. The applicants have developed a versatile approach to protect peptides that are truncated in the blood stream by proteases. By making custom-tailored minor appendages from a diverse range of suitable chemical moieties to the N-terminus of target peptides, substrate recognition by frontline proteases is abolished whereas interaction with cognate ligand receptors is not compromised. The goal of the current proposal is to identify optimal appendages for two promising hormone targets, growth hormone releasing hormone (GHRH) and peptide tyrosine tyrosine (PYY) that in combination with complementary peptide modifications could be medically exploited with availability of longer acting analogues. GHRH acts via a combination of growth hormone-dependent and -independent mechanisms that, among other potential benefits, have been shown to attenuate lipodystrophia in HIV patients. Furthermore, such compounds hold promise for the treatment of non-alcoholic steatohepatitis in the general population, a condition where better treatment options are urgently needed. PYY is an enteroendocrine hormone that, similar to highly successful incretin-based drugs, provides an opportunity to develop analogues for simultaneously treating type 2 diabetes and obesity. In addition to their promise as stand-alone drugs, long- acting PYY mimetics also offer an attractive option to synergize with leading incretin medications and thereby potentiate metabolic benefits of the latter while minimizing side effects. In an interdisciplinary collaboration between scientists in academia and biotechnology with expertise in medicinal chemistry, molecular pharmacology, and early in vivo studies, candidate peptide analogues for future preclinical development will be identified by pursuing 3 Specific Aims: (1) to identify optimized protease- resistant analogues of GHRH and PYY that retain full agonist activity, (2) to further protect these molecule from other proteases by side-chain acylations that are also known to delay clearance from the blood stream by complementary mechanisms, and (3) to assess serum half life of selected analogues following s.c. injection in mice, leading to the selection of one candidate and one backup each among tested GHRH and PYY analogues for future preclinical evaluation. Although beyond the scope of the proposed phase 1 proposal, the objective in an anticipated phase 2 follow-up will be to investigate safety and efficacy of candidates in animal models of NASH or diabesity as the basis for IND enabling studies.

项目概要 肽疗法结合了高效力和选择性，并且比传统疗法产生的副作用更少 小分子。这激发了人们对填补“生物制品”和小分子之间空白的肽的兴趣， 因为基于肽的化合物具有与其他类别不同的​​关键所需特性。一个专业 延长天然肽的短半衰期仍然是一项挑战，因为天然肽对快速酶敏感 催化水解裂解和失活。申请人开发了一种通用方法来保护 在血流中被蛋白酶截断的肽。通过制作定制的小附属物 从各种合适的化学部分到目标肽的 N 末端、底物识别 前线蛋白酶的作用被消除，而与同源配体受体的相互作用不受影响。 当前提案的目标是确定两个有希望的激素目标的最佳附件，即生长 激素释放激素（GHRH）和肽酪氨酸酪氨酸（PYY），与 互补肽修饰可以在医学上利用更长作用的类似物。 GHRH 通过生长激素依赖性和非依赖性机制的组合发挥作用，其中包括 潜在的好处已被证明可以减轻艾滋病毒患者的脂肪营养不良。此外，这样的 化合物有望治疗普通人群的非酒精性脂肪性肝炎 迫切需要更好的治疗方案的情况。 PYY 是一种肠内分泌激素， 类似于非常成功的肠促胰岛素药物，为开发类似物提供了机会 同时治疗2型糖尿病和肥胖症。除了作为独立药物的承诺外，长期 作用 PYY 模拟物还提供了一个有吸引力的选择，可以与领先的肠促胰岛素药物协同作用，从而 增强后者的代谢益处，同时最大限度地减少副作用。 在学术界和生物技术领域具有专业知识的科学家之间进行跨学科合作 药物化学、分子药理学和早期体内研究，未来的候选肽类似物 临床前开发将通过追求 3 个具体目标来确定：(1) 确定优化的蛋白酶- GHRH 和 PYY 的抗性类似物保留了完整的激动剂活性，(2) 进一步保护这些分子免受 通过侧链酰化作用的其他蛋白酶也被认为可以延迟从血流中的清除 补充机制，以及（3）评估皮下注射后所选类似物的血清半衰期。注入 小鼠，导致在测试的 GHRH 和 PYY 类似物中各选择一种候选物和一种备用物 用于未来的临床前评估。尽管超出了第一阶段提案的范围，但目标 预期的第二阶段后续行动将是在动物模型中研究候选药物的安全性和有效性 NASH 或糖尿病作为 IND 支持研究的基础。