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Introduction of Pro and Its Analogues in the Conserved P1 Position of Trypsin Inhibitor SFTI-1 Retains Its Inhibitory Activity

[ Vol. 18 , Issue. 11 ]

Author(s):

Anna Legowska, Dawid Debowski, Rafal Lukajtis, Emilia Sztabkowska, Aneta Mizeria, Krzysztof Brzozowski, Magdalena Wysocka, Adam Lesner and Krzysztof Rolka   Pages 1158 - 1167 ( 10 )

Abstract:


A number of monocyclic SFTI-1 analogues modified in the conserved inhibitor P1 position by Pro, its L-hydroxyproline (Hyp) derivative as well as mimetics with different ring size were synthesized by the solid-phase method. Replacement of Ser6 by Pro, Hyp, and a four-member ring, L-azetidine-2-carboxylic acid (Aze), retained trypsin or chymotrypsin inhibitory activity. The determined association equilibrium constants of these analogues with a cognate enzyme were about two orders of magnitude lower than those obtained for ones with conserved Ser6. In all analogues, with the exception of one, [Phe5,Aze6]SFTI-1, the P1-P1 reactive site remained intact. The results provide first evidence that the conserved Ser in the P1 position of Bowman-Birk inhibitors can be successfully replaced by an amino acid with a secondary amine group.

Keywords:

Peptides, proteinase inhibitors, SFTI-1, mimetics of Pro, BB, BBI, Fmoc, DCM, DMF/NMP, NPGB, MALDI MS, BAPNA, HPLC, Proteolytic susceptibilityPeptides, proteinase inhibitors, SFTI-1, mimetics of Pro, BB, BBI, Fmoc, DCM, DMF/NMP, NPGB, MALDI MS, BAPNA, HPLC, Proteolytic susceptibility

Affiliation:

Faculty of Chemistry, University of Gdansk, Sobieskiego 18, 80-952 Gdansk, Poland.



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