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Development of a Potent Wound Healing Agent Based on the Liver Fluke Granulin Structural Fold

2017; American Chemical Society; Volume: 60; Issue: 10 Linguagem: Inglês

10.1021/acs.jmedchem.7b00047

1520-4804

Paramjit S. Bansal, Michael J. Smout, David T. Wilson, Claudia Cobos Caceres, Mohadeseh Dastpeyman, Javier Sotillo, Julia Seifert, Paul J. Brindley, Alex Loukas, Norelle L. Daly,

Peptidase Inhibition and Analysis

Granulins are a family of protein growth factors that are involved in cell proliferation. An orthologue of granulin from the human parasitic liver fluke Opisthorchis viverrini, known as Ov-GRN-1, induces angiogenesis and accelerates wound repair. Recombinant Ov-GRN-1 production is complex and poses an obstacle for clinical development. To identify the bioactive region(s) of Ov-GRN-1, four truncated N-terminal analogues were synthesized and characterized structurally using NMR spectroscopy. Peptides that contained only two native disulfide bonds lack the characteristic granulin β-hairpin structure. Remarkably, the introduction of a non-native disulfide bond was critical for formation of β-hairpin structure. Despite this structural difference, both two and three disulfide-bonded peptides drove proliferation of a human cholangiocyte cell line and demonstrated potent wound healing in mice. Peptides derived from Ov-GRN-1 are leads for novel wound healing therapeutics, as they are likely less immunogenic than the full-length protein and more convenient to produce.