TY - JOUR
T1 - Structural Variants of a Liver Fluke Derived Granulin Peptide Potently Stimulate Wound Healing
AU - Dastpeyman, Mohadeseh
AU - Bansal, Paramjit S.
AU - Wilson, David
AU - Sotillo, Javier
AU - Brindley, Paul J.
AU - Loukas, Alex
AU - Smout, Michael J.
AU - Daly, Norelle L.
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/10/11
Y1 - 2018/10/11
N2 - Granulins are a family of growth factors involved in cell proliferation. The liver-fluke granulin, Ov-GRN-1, isolated from a carcinogenic liver fluke Opisthorchis viverrini, can significantly accelerate wound repair in vivo and in vitro. However, it is difficult to express Ov-GRN-1 in recombinant form at high yield, impeding its utility as a drug lead. Previously we reported that a truncated analogue (Ov-GRN12-35-3s) promotes healing of cutaneous wounds in mice. NMR analysis of this analogue indicates the presence of multiple conformations, most likely as a result of proline cis/trans isomerization. To further investigate whether the proline residues are involved in adopting the multiple confirmations, we have synthesized analogues involving mutation of the proline residues. We have shown that the proline residues have a significant influence on the structure, activity, and folding of Ov-GRN12-35-3s. These results provide insight into improving the oxidative folding yield and bioactivity of Ov-GRN12-35-3s and might facilitate the development of a novel wound healing agent.
AB - Granulins are a family of growth factors involved in cell proliferation. The liver-fluke granulin, Ov-GRN-1, isolated from a carcinogenic liver fluke Opisthorchis viverrini, can significantly accelerate wound repair in vivo and in vitro. However, it is difficult to express Ov-GRN-1 in recombinant form at high yield, impeding its utility as a drug lead. Previously we reported that a truncated analogue (Ov-GRN12-35-3s) promotes healing of cutaneous wounds in mice. NMR analysis of this analogue indicates the presence of multiple conformations, most likely as a result of proline cis/trans isomerization. To further investigate whether the proline residues are involved in adopting the multiple confirmations, we have synthesized analogues involving mutation of the proline residues. We have shown that the proline residues have a significant influence on the structure, activity, and folding of Ov-GRN12-35-3s. These results provide insight into improving the oxidative folding yield and bioactivity of Ov-GRN12-35-3s and might facilitate the development of a novel wound healing agent.
UR - http://www.scopus.com/inward/record.url?scp=85054128269&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b00898
DO - 10.1021/acs.jmedchem.8b00898
M3 - Article
C2 - 30183294
AN - SCOPUS:85054128269
SN - 0022-2623
VL - 61
SP - 8746
EP - 8753
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 19
ER -