Protease Stable N-Terminally Modified Therapeutic Peptides

项目摘要 肽类药物联合收割机结合了高效性和选择性，并且比传统的切割机产生更少的副作用。 小分子。这激发了人们对填补“生物制品”和小分子之间差距的肽的兴趣， 因为基于肽的化合物具有与其它两类不同的关键的所需性质。一个主要 挑战仍然是延长天然肽的短半衰期，天然肽对快速酶敏感， 催化水解裂解和失活。申请人开发了一种多功能的方法来保护 在血流中被蛋白酶截短的肽。通过制作定制的小附件 从多种合适的化学部分到靶肽的N-末端，底物识别 而与同源配体受体的相互作用不受损害。 目前的建议的目标是确定两个有前途的激素目标，生长的最佳附属物 激素释放激素（GHRH）和肽酪氨酸酪氨酸（PYY）， 互补肽修饰可以在医学上利用更长效类似物的可用性。 GHRH通过生长激素依赖性和非依赖性机制的组合起作用， 潜在的益处，已经显示出减弱HIV患者的脂肪代谢障碍。此外，这种 化合物有望用于治疗一般人群中的非酒精性脂肪性肝炎， 迫切需要更好的治疗方案。PYY是一种肠内分泌激素， 类似于非常成功的肠促胰岛素类药物，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，长期以来， 作用PYY模拟物还提供了与主要肠促胰岛素药物协同作用的有吸引力的选择， 增强后者的代谢益处，同时使副作用最小化。 在学术界和生物技术科学家之间的跨学科合作中， 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- 保留完全激动剂活性的GHRH和PYY的抗性类似物，（2）进一步保护这些分子免受 其它蛋白酶通过侧链酰化作用也已知通过 补充机制，和（3）评估s.c.注射 小鼠，导致在测试的GHRH和PYY类似物中各选择一个候选物和一个备用物 用于未来的临床前评价。尽管超出了拟议的第一阶段提案的范围， 预期的第二阶段随访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启动研究的基础。

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.