Synthesis of Stable Substance P Analog using Sunflower Trypsin Inhibitor Scaffold
Substance P is a neuropeptide associated with pain and inflammatory signaling pathways. It is the ligand of neurokinin-1 receptor (NK1R). Some analogs of substance P that act as NK1R antagonist can be used as a drug to manage pain and inflammation. However, being a linear peptide they are not resistant to enzyme degradation and thus not orally active. To overcome this challenge, we synthesize a stable NK1R antagonist by grafting a linear 7-residue NK1R antagonist derived from the N-terminal sequence of substance P into the cyclic sunflower trypsin inhibitor-1 (SFTI-1) scaffold. This chimeric peptide SFSP(N) possesses two functions, trypsin inhibition and neurokinin-1 receptor (NK1R) inhibition. Trypsin inhibition is derived from trypsin inhibitory binding loop domain of cyclic sunflower trypsin inhibitor-1, while NK1R antagonism is derived from the N-terminal fragment of linear substance P. Consequently, the cyclic SFSP(N) is bifunctional and gains resistance against heating, pH and trypsin treatment. Based on the design and synthesis of stable NK1R antagonist adopting cyclized backbone and intramolecular disulfide constrains, we can prepare orally active peptidyl drugs to treat pain and inflammation.