Bansal, Paramjit S., Smout, Michael J., Wilson, David, Cobos Caceres, Claudia, Dastpeyman, Mohadeseh, Sotillo, Javier, Seifert, Julia, Brindley, Paul J., Loukas, Alex, and Daly, Norelle L. (2017) Development of a potent wound healing agent based on the liver fluke granulin structural fold. Journal of Medicinal Chemistry, 60 (10). pp. 4258-4266.

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Abstract

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.

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