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Introduction of non-natural amino acid residues into the substrate-specific P1 position of trypsin inhibitor SFTI-1 yields potent chymotrypsin and cathepsin G inhibitors.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2009 May 01; Vol. 17 (9), pp. 3302-7. Date of Electronic Publication: 2009 Mar 27. - Publication Year :
- 2009
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Abstract
- A series of trypsin inhibitor SFTI-1compounds modified in substrate-specific P(1) position was synthesized by the solid-phase method. Lys5 present in the wild inhibitor was replaced by Phe derivatives substituted in para position of the phenyl ring, l-pyridylalanine and N-4-nitrobenzylgycine. Their inhibitory activities with bovine alpha-chymotrypsin and cathepsin G were estimated by determination of association equilibrium constants (K(a)). All analogues inhibited bovine alpha-chymotrypsin. The highest inihbitory activity displayed peptides with the fluorine, nitro and methyl substituents. They were 13-15-fold more active than [Phe(5)]SFTI-1 used as a reference. They are the most potent chymotrypsin inhibitors of this size. Substitution of Lys5 by Phe did not change the cathepsin G inhibitory activity. Introduction of Phe(p-F), Phe(p-NH(2)) and Phe(p-CH(3)) in this position retained the affinity towards this proteinase, whereas Phe(p-guanidine) gave an inhibitor more than twice as active, which appeared to be stable in human serum. On the other hand, a peptomeric analogue with N-4-nitrobenzylglycine failed to inhibit cathepsin G. Despite the fact the introduced amino acids were non-coded, the peptide bonds formed by them were hydrolyzed by chymotrypsin. We postulate that additional interaction of para-substitutents with the enzyme are responsible for the enhanced inhibitory activity of the analogues.
- Subjects :
- Amino Acid Sequence
Amino Acids metabolism
Animals
Cattle
Chymotrypsin chemistry
Chymotrypsin metabolism
Humans
Molecular Sequence Data
Peptides chemistry
Peptides pharmacology
Peptides, Cyclic pharmacology
Structure-Activity Relationship
Substrate Specificity
Amino Acids chemistry
Cathepsin G antagonists & inhibitors
Chymotrypsin antagonists & inhibitors
Enzyme Inhibitors chemistry
Peptides, Cyclic chemistry
Trypsin Inhibitors chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 17
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19362846
- Full Text :
- https://doi.org/10.1016/j.bmc.2009.03.045