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KMID : 1094720000050010061
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Biotechnology and Bioprocess Engineering
2000 Volume.5 No. 1 p.61 ~ p.64
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Inhibition of prolyl 4-hydroxylase by oxaproline tetrapeptidesin vitro and mass analysis for the enzymatic reaction products
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Moon Hong-Sik
Begley Tedhg P.
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Abstract
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A series of 5-oxaproline peptide derivatives was synthesized and evaluated for its ability to inhibit the prolyl 4-hydroxylasein vitro. Structure-activity studies show that the 5-oxaproline sequences, prepared by the 1,3-dipolar cycloaddition of the C-methoxycarbonyl-N-mannosyl nitrone in the presence of the ethylene, are more active than the corresponding proline derivatives. Prolyl 4-hydroxylase belongs to a family of Fe2+-dependent dioxygenase, which catalyzes the formation of 4-hydroxyproline in collagens by the hydroxylation of proline residues in-Gly-Xaa-Pro-Gly- of procollagen chains. In this paper we discover the more selective N-Cbz-Gly-Phe-Pro-Gly-OEt (K m=520 μM) sequences which are showed stronger binding than othersin vitro. Therefore, we set out to investigate constrained tetrapeptide that was designed to mimic the proline structure of peptides for the development of prolyl 4-hydroxylase inhibitor. From this result, we found that the most potent inhibitor is N-Dansyl-Gly-Phe-5-oxaPro-Gly-OEt (K i=1.6 μM). This has prompted attempts to develop drugs which inhibit collagen synthesis. Prolyl 4-hydroxylase would seem a particularly suitable target for antifibrotic therapy.
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KEYWORD
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oxaproline, prolyl 4-hydroxylase, collagen, antifibrotic therapy
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