title: Examples of peptide-peptoid hybrid serine protease inhibitors based on the trypsin inhibitor SFTI-1 with complete protease resistance at the P1-P1' reactive site.
abstract: Research in the field of protease inhibitors is focused on obtaining potent, specific and protease-resistant inhibitors. To our knowledge, there are no reports in the literature that consider the application of N-substituted glycine residues (peptoid monomers) for the design of peptidomimetic protease inhibitors. We hereby present the chemical synthesis and kinetic properties of two new analogues of the trypsin inhibitor SFTI-1 modified at the P1 position. Substitution of Lys5 in SFTI-1 by N-(4-aminobutyl)-glycine and N-benzylglycine, which mimic Lys and Phe, respectively, made these analogues completely protease-resistant at their P1-P1' reactive sites. The analogues synthesised appeared to be potent inhibitors of bovine beta-trypsin and alpha-chymotrypsin. These noncovalent, competitive and selective peptide-peptoid hybrid (peptomeric) inhibitors might open the way to targeting unwanted proteolysis.
authors.affiliation: Department of Bioorganic Chemistry, Faculty of Chemistry, University of Gdansk, Sobieskiego 18 St., 80-523 Gdansk, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Stawikowski
authors.forename: Roma
authors.initials: R
authors.lastname: Stawikowska
authors.forename: Anna
authors.initials: A
authors.lastname: Jaśkiewicz
authors.forename: Ewa
authors.initials: E
authors.lastname: Zabłotna
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Rolka
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002417:Cattle; D002918:Chymotrypsin / Q000378:metabolism; D005998:Glycine / Q000737:chemistry; D008239:Lysine / Q000737:chemistry; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D034444:Peptoids / Q000737:chemistry* / Q000378:metabolism; D010649:Phenylalanine / Q000737:chemistry; D050767:Qc-SNARE Proteins; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014357:Trypsin / Q000378:metabolism; D014361:Trypsin Inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D010455:Peptides; D034444:Peptoids; D050767:Qc-SNARE Proteins; C094380:SFT1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D015842:Serine Proteinase Inhibitors; D014361:Trypsin Inhibitors; D010649:Phenylalanine; D002918:Chymotrypsin; C117608:alpha-chymotrypsin; D014357:Trypsin; D008239:Lysine; D005998:Glycine