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.

项目总结 多肽疗法结合了高效和选择性，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多肽的兴趣， 因为基于多肽的化合物具有与其他两类不同的关键的所需性质。一位少校 延长天然多肽的短半衰期仍然是一个挑战，因为天然多肽对快速酶敏感。 催化的水解性切割和失活。申请者开发了一种通用的方法来保护 在血流中被蛋白质酶截断的多肽。通过制作定制的小附件 从各种合适的化学部分到靶肽的N-端，底物识别 前线的蛋白水解酶被取消，而与同源配体受体的相互作用不受影响。 当前提案的目标是为两个有希望的荷尔蒙目标--生长--确定最佳的附件 激素释放激素(GHRH)和多肽酪氨酸(PYY)与 随着作用时间更长的类似物的出现，互补的多肽修饰可以在医学上得到开发。 GHRH通过生长激素依赖和非依赖机制的组合发挥作用，其中包括 潜在的益处，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 化合物有望在普通人群中治疗非酒精性脂肪性肝炎。 迫切需要更好的治疗选择的情况。PYY是一种肠内分泌激素， 类似于非常成功的基于胰岛素的药物，提供了一个开发类似物的机会 同时治疗2型糖尿病和肥胖症。除了它们作为独立药物的承诺外，长期- 作用PYY模拟物也提供了一个有吸引力的选择，可以与领先的胰岛素药物协同作用，从而 强化后者的新陈代谢益处，同时将副作用降至最低。 在学术界和生物技术科学家之间的跨学科合作中，他们拥有 药物化学、分子药理学和早期体内研究，未来的候选多肽类似物 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- 保持完全激动剂活性的GHRH和PYY的抗性类似物，(2)进一步保护这些分子不受 其他通过侧链酰化的蛋白酶，也已知通过以下方式延迟血流的清除 互补机制，以及(3)评估S.C.后选定类似物的血清半衰期。注入 小鼠，导致在测试的GHRH和PYY类似物中各选择一个候选和一个备份 用于未来的临床前评估。虽然超出了拟议的第一阶段提案的范围，但 预期的第二阶段后续研究将在动物模型中调查候选药物的安全性和有效性。 NASH或肥胖作为IND使能研究的基础。