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

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    Development of a Potent Wound Healing Agent Based on the Liver Fluke Granulin Structural Fold
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    † Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns 4870, Queensland Australia
    ‡ Department of Microbiology, Immunology and Tropical Medicine and Research Center for Neglected Diseases of Poverty, School of Medicine and Health Sciences, George Washington University, Washington D.C. 20037, United States
    *For N.L.D.: phone, +61-7-4232 1815; E-mail, [email protected]
    *For A.L.: phone, +61-7-4232 1608; E-mail, [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2017, 60, 10, 4258–4266
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    https://doi.org/10.1021/acs.jmedchem.7b00047
    Published April 20, 2017
    Copyright © 2017 American Chemical Society
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    Abstract

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    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.

    Copyright © 2017 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b00047.

    • Structure statistics for Ov-GRN12–34 and Ov-GRN12–35_3s; chemical shift analysis of carp granulin-1; analysis of different disulfide connectivities for Ov-GRN12–35_3s; wound healing photos (PDF)

    • Ov-GRN12–34 (PDB)

    • Ov-GRN12–35 (PDB)

    • PDB 1QGM (PDB)

    Accession Codes

    The PDB ID codes are 5UJH and 5UJG for Ov-GRN12–34 and Ov-GRN12–35_3s, respectively. Authors will release the atomics coordinates and experimental data upon article publication.

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

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    Cite this: J. Med. Chem. 2017, 60, 10, 4258–4266
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.7b00047
    Published April 20, 2017
    Copyright © 2017 American Chemical Society
    Request reuse permissions

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