Pinocembrin and its linolenoyl ester derivative induce wound healing activity in HaCaT cell line potentially involving a GPR120/FFA4 mediated pathway

Sarah Mazzotta; Paolo Governa; Vittoria Borgonetti; Paola Marcolongo; Claudio Nanni; Alessandra Gamberucci; Fabrizio Manetti; Federica Pessina; Gabriele Carullo; Antonella Brizzi; Francesca Aiello

doi:10.1016/j.bioorg.2021.104657

Pinocembrin and its linolenoyl ester derivative induce wound healing activity in HaCaT cell line potentially involving a GPR120/FFA4 mediated pathway

Bioorg Chem. 2021 Mar:108:104657. doi: 10.1016/j.bioorg.2021.104657. Epub 2021 Jan 27.

Authors

Affiliations

¹ Department of Pharmaceutical Sciences, Via Luigi Mangiagalli 25, 20133 Milano, Italy.
² Department of Biotechnology, Chemistry and Pharmacy - DoE 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
³ Department of Neuroscience, Psychology, Pharmacology and Child Health (NEUROFARBA), University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy.
⁴ Department of Molecular and Developmental Medicine, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
⁵ Department of Biotechnology, Chemistry and Pharmacy - DoE 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy. Electronic address: fabrizio.manetti@unisi.it.
⁶ Department of Molecular and Developmental Medicine, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy. Electronic address: federica.pessina@unisi.it.
⁷ Department of Biotechnology, Chemistry and Pharmacy - DoE 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy. Electronic address: gabriele.carullo@unisi.it.
⁸ Department of Pharmacy, Health and Nutritional Sciences - DoE 2018-2022, University of Calabria, Ed. Polifunzionale, 87036 Arcavacata di Rende (CS), Italy.

PMID: 33556697
DOI: 10.1016/j.bioorg.2021.104657

Abstract

Wound healing represents an urgent need from the clinical point of view. Several diseases result in wound conditions which are difficult to treat, such as in the case of diabetic foot ulcer. Starting from there, the medicinal research has focused on various targets over the years, including GPCRs as new wound healing drug targets. In line with this, GPR120, known to be an attractive target in type 2 diabetes drug discovery, was studied to finalize the development of new wound healing agents. Pinocembrin (HW0) was evaluated as a suitable compound for interacting with GPR120, and was hybridized with fatty acids, which are known endogenous GPR120 ligands, to enhance the wound healing potential and GPR120 interactions. HW0 and its 7-linolenoyl derivative (HW3) were found to be innovative wound healing agents. Immunofluorescence and functional assays suggested that their activity was mediated by GPR120, and docking simulations showed that the compounds could share the same pocket occupied by the known GPR120 agonist, TUG-891.

Keywords: FFA4; GPR120; HaCaT cell line; Molecular docking; PUFAs; Pancreatic porcine lipase; Pinocembrin; TUG-891; Wound healing; β-arrestin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Survival / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Esters / chemical synthesis
Esters / chemistry
Esters / pharmacology*
Flavanones / chemical synthesis
Flavanones / chemistry
Flavanones / pharmacology*
Humans
Linolenic Acids / chemical synthesis
Linolenic Acids / chemistry
Linolenic Acids / pharmacology*
Molecular Docking Simulation
Molecular Structure
Receptors, G-Protein-Coupled / metabolism*
Structure-Activity Relationship
Wound Healing / drug effects*

Substances

Esters
FFAR4 protein, human
Flavanones
Linolenic Acids
Receptors, G-Protein-Coupled
pinocembrin