Selection of peptomeric inhibitors of bovine alpha-chymotrypsin and cathepsin G based on trypsin inhibitor SFTI-1 using a combinatorial chemistry approach.
A peptomeric library consisting of 360 monocyclic analogues of trypsin inhibitor SFTI-1 isolated from sunflower seeds was designed and synthesized by a solid-phase approach in order to select chymotrypsin and cathepsin G inhibitors. All peptomers contained a proteinogenic-Phe-mimicking N-benzylglycine (Nphe) at positions 5 and 12. Into the synthesized library, different peptoid monomers were introduced in the 7-10 segment. Deconvolution of the library against both proteinases through an iterative method in solution revealed that the strongest chymotrypsin inhibitory activity was displayed by two analogues, [Nphe(5,12)]SFTI-1 (1) and [Nphe(5,12), Naem(8)]SFTI-1 (2), where Naem stands for N-(2-morpholinoethyl)glycine. After deconvolution against a cathepsin G analogue, [Nphe(5,12), Npip(8,9), Nnle(10)] SFTI-1 (3) (Npip = N-(3,4-methylenedioxybenzyl)glycine) appeared to be the most potent inhibitor with a high serum stability. It is worth noting that the analogues obtained by a combinatorial approach display high specificity towards one of the experimental enzymes. Another interesting feature is the lack of Pro8 in analogues 2 and 3, the amino acid residue absolutely conserved in the family of Bownan-Birk inhibitors.
Łegowska
Anna
A
Faculty of Chemistry, University of Gdańsk, Sobieskiego 18, Gdańsk, 80-952, Poland. legowska@chem.univ.gda.pl
Debowski
Dawid
D
Lesner
Adam
A
Wysocka
Magdalena
M
Rolka
Krzysztof
K
D000818:Animals; D056649:Cathepsin G / Q000037:antagonists & inhibitors* / Q000235:genetics; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D002918:Chymotrypsin / Q000037:antagonists & inhibitors* / Q000235:genetics; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D019295:Computational Biology / Q000379:methods; D005998:Glycine / Q000737:chemistry; D006801:Humans; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000235:genetics; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000235:genetics; D014361:Trypsin Inhibitors / Q000737:chemistry* / Q000235:genetics
D019151:Peptide Library; D010455:Peptides; D010456:Peptides, Cyclic; C448501:SFTI-1 peptide, sunflower; D014361:Trypsin Inhibitors; D002918:Chymotrypsin; C117608:alpha-chymotrypsin; D056649:Cathepsin G; D005998:Glycine