Addressing the Problems of Traditional Peptide Therapeutic Agents

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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.