Addressing the Problems of Traditional Peptide Therapeutic Agents

基于多肽的治疗剂作为一种治疗多种疾病的方法，近年来受到了广泛的关注。事实上，用人体自身合成的化合物来治疗疾病的概念是一个很有吸引力的概念，因为这些化合物将是高度活跃的，而且在过去的二十年里，肽合成的进步已经使小肽和蛋白质的合成几乎成为一种常规的锻炼。然而，在临床中利用这些肽的数量相对较少。尽管在体外具有良好的活性，但许多多肽遭受代谢降解，特别是在口服时。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。我们将通过基于磺胺单元的不可水解基序取代易感键来解决这个问题。磺胺基序先前已被证明是肽键的良好模拟物（没有明显的生物活性损失），对水解酶具有更高的稳定性。然而，到目前为止，它们还没有成功地包括在肽序列中，以增加其稳定性。在我们的研究过程中，我们将采用一些新颖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，这些方法在制备高功能化有机化合物方面显示出最近的希望。

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.