Sunflower trypsin inhibitor
Sunflower trypsin inhibitor (SFTI) is a small, circular peptide produced in sunflower seeds, and is a potent inhibitor of trypsin. It is the smallest known member of the Bowman-Birk family of serine protease inhibitors.[1]
One example of Sunflower trypsin inhibitor is Sunflower trypsin inhibitor-1 (SFTI-1). Sunflower trypsin inhibitor-1 is a potent Bowman-Birk inhibitor. Sunflower trypsin inhibitor-1 is the simplest cysteine-rich peptide scaffold because it is a bicyclic 14 amino acid peptide and only has one disulfide bond. The disulfide bond divides the peptide into two loops. One loop is a functional trypsin inhibitory and the second loop is a nonfunctional loop.[2] The nonfunctional loop can be replaced by a bioactive loop. It is extracted from a seed of a sunflower called Helianthus annuus. The synthesis of SFTI is not known however, it can evolutionarily linked to a gene-coded product from classic Bowman-Birk inhibitors.[3] STFI is used in radiopharmaceutical, antimicrobial, and pro-angiogenic peptides.[2]
Synthetic inhibitors and the structure of SFTI
By modifying the amino acid sequence of sunflower trypsin inhibitor, more specifically, sunflower trypsin inhibitor-1 (SFTI-1), researchers have been able to develop synthetic serine protease inhibitors that have specificity and improved inhibitory activity towards certain serine proteases that are found in the human body, such as tissue kallikreins and human matriptase-1. For instance, researchers from the Institute of Child Health and the Department of Chemistry of the University College London, have created two SFTI-1 analogs (I10G and I10H) by substituting residue 10 of SFTI-1 (isoleucine, I) with glycine (G) and histidine (H), respectively. Out of the two analogs, SFTI-I10H was found to be the more potent KLK5 inhibitor.[4] Another group of researchers from the previously mentioned institute and department of the University College London, conducted further research on the development of synthetic kallikrein inhibitors by modifying the amino acid sequence of SFTI-I10H. Out of the six SFTI-I10H variants that were constructed by modifying SFTI-I10H, the first and second variant (K5R_I10H and I10H_F12W) demonstrated improved KLK5 inhibition and the sixth variant (K5R_I10H_F12W) showed dual-inhibition of KLK5 and KLK7, improved KLK5 inhibition potency, and specificity for KLK5 and KLK14. The first variant (K5R_I10H) was made by replacing residue 5 of SFTI-I10H (lysine, K) with arginine (R), and in order to get the second variant (I10H_F12W) residue 12 (phenylalanine, F) was replaced with tryptophan (W). Lastly, the sixth variant (K5R_I10H_F12W) was developed by combining the amino acid substitutions of the first and second variants.[5]
Moreover, researchers from the Clemens-Schöpf Institute of Organic Chemistry and Biochemistry and Helmholtz-Institute for Pharmaceutical Research Saarland, developed potent synthetic human matriptase-1 inhibitors based on a different SFTI-1 variant, SDMI-1. SFTI-1 derived matriptase inhibitor-1 (SDMI-1) was previously developed by replacing residue 10 of SFTI-1 (isoleucine, I) with arginine (R) and residue 12 (phenylalanine, F) with histidine (H). Further modifications of SDMI-1 resulted in synthetic matriptase-1 inhibitors with improved inhibitory activity, matriptase binding, and inhibition potency. The SDMI-1 variant that resulted in enhanced inhibitory activity was developed by replacing residue 1 of SDMI-1 (glycine, G) with lysine (K) and by keeping it as a monocyclic structure. The SDMI-1 variant that resulted in improved matriptase binding was created by using the same amino acid substitutions of the previously mentioned SDMI-1 variant and by attaching a bulky fluorescein moiety to the side chain of lysine. Lastly, the SDMI-1 variant that had enhanced inhibition potency was developed by applying the same amino acid substitutions of the previous variants, cleaving the proline-aspartic acid sequence found at the C-terminus (PD-OH), and by making it a bicyclic compound via tail-to-side-chain cyclization.[6]
See also
References
- ^ Luckett S, Garcia RS, Barker JJ, Konarev AV, Shewry PR, Clarke AR, Brady RL (July 1999). "High-resolution structure of a potent, cyclic proteinase inhibitor from sunflower seeds". Journal of Molecular Biology. 290 (2): 525–33. doi:10.1006/jmbi.1999.2891. PMID 10390350.
- ^ a b Qiu Y, Taichi M, Wei N, Yang H, Luo KQ, Tam JP (January 2017). "1 Receptor Antagonist Engineered as a Bifunctional Chimera of Sunflower Trypsin Inhibitor". Journal of Medicinal Chemistry. 60 (1): 504–510. doi:10.1021/acs.jmedchem.6b01011. PMID 27977181.
- ^ Korsinczky ML, Schirra HJ, Craik DJ (October 2004). "Sunflower trypsin inhibitor-1". Current Protein & Peptide Science. 5 (5): 351–64. doi:10.2174/1389203043379594. PMID 15544530.
- ^ Shariff, Leila; Zhu, Yanan; Cowper, Ben; Di, Wei-Li; Macmillan, Derek (2014-10-21). "Sunflower trypsin inhibitor (SFTI-1) analogues of synthetic and biological origin via N→S acyl transfer: potential inhibitors of human Kallikrein-5 (KLK5)". Tetrahedron. 70 (42): 7675–7680. doi:10.1016/j.tet.2014.06.059.
- ^ Chen W, Kinsler VA, Macmillan D, Di WL (2016-11-08). "Tissue Kallikrein Inhibitors Based on the Sunflower Trypsin Inhibitor Scaffold - A Potential Therapeutic Intervention for Skin Diseases". PLOS ONE. 11 (11): e0166268. Bibcode:2016PLoSO..1166268C. doi:10.1371/journal.pone.0166268. PMC 5100903. PMID 27824929.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Fittler H, Avrutina O, Empting M, Kolmar H (June 2014). "Potent inhibitors of human matriptase-1 based on the scaffold of sunflower trypsin inhibitor". Journal of Peptide Science. 20 (6): 415–20. doi:10.1002/psc.2629. PMID 24723440. S2CID 21635664.
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