Development of a potent wound healing agent based on the liver fluke granulin structural fold

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.

Item ID: 51745
Item Type: Article (Research - C1)
ISSN: 1520-4804
Funders: National Cancer Institute (NCI), National Health and Medical Research Council (NHMRC), Australian Research Council (ARC)
Projects and Grants: NCI R01CA164719, NHMRC 1037304, NHMRC 1020114, ARC FF110100226
Date Deposited: 11 Dec 2017 04:31
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110106 Medical Biochemistry: Proteins and Peptides (incl Medical Proteomics) @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 100%
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