Synthesis of Stable Substance P Analog using Sunflower Trypsin Inhibitor Scaffold
ثبت نشده
چکیده
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.
منابع مشابه
Sunflower Trypsin Inhibitor-1: Chemical v. Biological Synthesis
Diverse gene-encoded cyclic peptides are produced by species from all three domains of life. The 14-residue, head-to-tail cyclized plant peptide, SFTI-1 (Sunflower Trypsin Inhibitor 1) [1] (Figure 1) has attracted much attention due to its great stability and capability to potently inhibit trypsin (Ki 0.1 nM) as well as the epithelial serine protease matriptase (Ki 0.92 nM) [2], giving it excit...
متن کاملEngineering pro-angiogenic peptides using stable, disulfide-rich cyclic scaffolds.
Fragments from the extracellular matrix proteins laminin and osteopontin and a sequence from VEGF have potent proangiogenic activity despite their small size (< 10 residues). However, these linear peptides have limited potential as drug candidates for therapeutic angiogenesis because of their poor stability. In the present study, we show that the therapeutic potential of these peptides can be s...
متن کاملTissue Kallikrein Inhibitors Based on the Sunflower Trypsin Inhibitor Scaffold – A Potential Therapeutic Intervention for Skin Diseases
Tissue kallikreins (KLKs), in particular KLK5, 7 and 14 are the major serine proteases in the skin responsible for skin shedding and activation of inflammatory cell signaling. In the normal skin, their activities are controlled by an endogenous protein protease inhibitor encoded by the SPINK5 gene. Loss-of-function mutations in SPINK5 leads to enhanced skin kallikrein activities and cause the s...
متن کاملDiscovery, structural determination, and putative processing of the precursor protein that produces the cyclic trypsin inhibitor sunflower trypsin inhibitor 1.
Backbone-cyclized proteins are becoming increasingly well known, although the mechanism by which they are processed from linear precursors is poorly understood. In this report the sequence and structure of the linear precursor of a cyclic trypsin inhibitor, sunflower trypsin inhibitor 1 (SFTI-1) from sunflower seeds, is described. The structure indicates that the major elements of the reactive ...
متن کاملSunflower trypsin inhibitor (SFTI-1) analogues of synthetic and biological origin via NS acyl transfer: potential inhibitors of human Kallikrein-5 (KLK5)
Sunflower Trypsin Inhibitor (SFTI-1) analogues have been prepared from simple linear precursors produced either by chemical synthesis or following purification from Escherichia coli. We have shown, for the first time that these linear SFTI-1 derived peptide sequences can be converted to circular peptides via selective consecutive acyl transfer reactions, and that the products derived from synth...
متن کامل