TY - JOUR
T1 - Development of a Potent Wound Healing Agent Based on the Liver Fluke Granulin Structural Fold
AU - Bansal, Paramjit S.
AU - Smout, Michael J.
AU - Wilson, David
AU - Cobos Caceres, Claudia
AU - Dastpeyman, Mohadeseh
AU - Sotillo, Javier
AU - Seifert, Julia
AU - Brindley, Paul J.
AU - Loukas, Alex
AU - Daly, Norelle L.
N1 - Funding Information:
This research was supported by an R01 grant from the National Cancer Institute, USA (R01CA164719), and a program grant from National Health and Medical Research Council, Australia (NHMRC) (1037304). Fellowship support was provided to A.L. from NHMRC (1020114) and N.L.D. from the Australian Research Council (FF110100226). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/5/25
Y1 - 2017/5/25
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85019750751
U2 - 10.1021/acs.jmedchem.7b00047
DO - 10.1021/acs.jmedchem.7b00047
M3 - Article
C2 - 28425707
AN - SCOPUS:85019750751
SN - 0022-2623
VL - 60
SP - 4258
EP - 4266
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 10
ER -