Addressing the Problems of Traditional Peptide Therapeutic Agents

解决传统肽治疗剂的问题

• 批准号: EP/D076161/1
• 负责人: Jonathan Wilden
• 金额: $ 20.7万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FD076161%2F1
• 关键词: Addressing; Problems; Traditional; Peptide; Therapeutic

Therapeutic agents based on peptides have received much attention in recent years as a method of treating various diseases. Indeed, the concept of treating disease with the compounds that the body itself synthesises is an attractive one, since the compounds will be highly active and advances in peptide synthesis in the last twenty years has made the synthesis of small peptides and proteins almost a routine exercise.The number of these peptides exploited in the clinic however is relatively few. Despite promising in vitro activity, a great many peptides suffer from metabolic degradation, particularly when administered orally. The difficulty in this situation emerges as the propensity of these compounds to be hydrolysed in the digestive system. In particular, proteolytic enzymes in the gut can degrade these peptides by recognising a particular site in their amino-acid sequence.We will address this problem by replacing the susceptible linkages with non-hydrolysable motifs based on a sulfonamide unit. The sulfonamide motif has been shown previously to be a good mimetic of the peptide bond (without significant loss in biological activity) with increased stability towards hydrolytic enzymes. Until now however, they have not successfully been included in a peptide sequence with a view to increasing its stability.In the course of our research, we will employ a number of novel approaches to achieve our goal. In particular we will investigate new synthetic methods in the field of organoindium chemistry which has shown recent promise in the preparation of highly functionalised organic compounds.

近年来，基于肽的治疗剂作为治疗各种疾病的方法受到了广泛关注。事实上，用人体自身合成的化合物治疗疾病的概念是一个有吸引力的概念，因为这些化合物将具有高度活性，而且近20年来肽合成的进展使小肽和蛋白质的合成几乎成为一项常规工作，但临床上使用的这些肽的数量相对较少。尽管在体外活性方面有希望，但许多肽遭受代谢降解，特别是当口服给药时。在这种情况下出现的困难是这些化合物在消化系统中被水解的倾向。特别是，肠道中的蛋白水解酶可以通过识别氨基酸序列中的特定位点来降解这些肽，我们将通过用基于磺酰胺单元的不可水解基序取代敏感键来解决这个问题。磺酰胺基序先前已被证明是肽键的良好模拟物（没有显著的生物活性损失），对水解酶具有增加的稳定性。然而，到目前为止，还没有成功地将它们包含在肽序列中以增加其稳定性。在我们的研究过程中，我们将采用一些新的方法来实现我们的目标。特别是，我们将研究有机铟化学领域的新合成方法，这些方法最近在制备高度官能化的有机化合物方面显示出了希望。