Design and synthesis of cyclotides as druggable biologics.

Abstract

Chronic pain is a universal health issue suffered by millions of patients. Current common treatments such as opiates and non-steroidal anti-inflammatory drugs remain problematic due to their side effects of different kinds and intensity. In this thesis, an alternative approach is established by blocking the key mediators of chronic pain and inflammation, the bradykinin B1 receptors. Bradykinin is secreted during cell injury, and the degradation ofbradykinin by kininase II forming the des-Arg9-bradykinin. They are the key mediators in pain response. Many bradykinin peptide antagonists have been developed and shown significant inhibition on both acute and chronic pains. However, the present bradykinin peptide antagonists are generally not suitable to be administrated orally. Here, we demonstrate the use of an unusual peptide scaffold named cyclotide, to achieve stability as well as oral bioavailability. Cyclotide, a plant-derived peptide, contains three intramolecular disulfide bonds and an end-to-end cyclic structure. The high proportion of hydrophobic residues together with the tightly packed disulfide core form an inverse side- chain configuration. Thus, gut absorption becomes possible and makes them a potential candidate in the development of orally active peptide drugs.