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Selection of peptomeric inhibitors of bovine α-chymotrypsin and cathepsin G based on trypsin inhibitor SFTI-1 using a combinatorial chemistry approach

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Abstract

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, [Nphe5,12]SFTI-1 (1) and [Nphe5,12, Naem8]SFTI-1 (2), where Naem stands for N-(2-morpholinoethyl)glycine. After deconvolution against a cathepsin G analogue, [Nphe5,12, Npip8,9, Nnle10] 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.

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Authors and Affiliations

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

    Anna Łęgowska, Dawid Dębowski, Adam Lesner, Magdalena Wysocka & Krzysztof Rolka

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  1. Anna Łęgowska
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  2. Dawid Dębowski
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  3. Adam Lesner
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  4. Magdalena Wysocka
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  5. Krzysztof Rolka
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Correspondence to Anna Łęgowska.

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Łęgowska, A., Dębowski, D., Lesner, A. et al. Selection of peptomeric inhibitors of bovine α-chymotrypsin and cathepsin G based on trypsin inhibitor SFTI-1 using a combinatorial chemistry approach. Mol Divers 14, 51–58 (2010). https://doi.org/10.1007/s11030-009-9142-z

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