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

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

Volume: 18 Issue: 11

Author(s): Anna Legowska, Dawid Debowski, Rafal Lukajtis, Emilia Sztabkowska, Aneta Mizeria, Krzysztof Brzozowski, Magdalena Wysocka, Adam Lesner and Krzysztof Rolka

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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

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.

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Legowska Anna, Debowski Dawid, Lukajtis Rafal, Sztabkowska Emilia, Mizeria Aneta, Brzozowski Krzysztof, Wysocka Magdalena, Lesner Adam and Rolka Krzysztof, Introduction of Pro and Its Analogues in the Conserved P1 Position of Trypsin Inhibitor SFTI-1 Retains Its Inhibitory Activity, Protein & Peptide Letters 2011; 18 (11) . https://dx.doi.org/10.2174/092986611797201002