Abstract

Scarring is a lifelong consequence of skin injury, with scar stiffness and poor appearance presenting physical and psychological barriers to a return to normal life. Lysyl oxidases are a family of enzymes that play a critical role in scar formation and maintenance. Lysyl oxidases stabilize the main component of scar tissue, collagen, and drive scar stiffness and appearance. Here we describe the development and characterisation of an irreversible lysyl oxidase inhibitor, PXS-6302. PXS-6302 is ideally suited for skin treatment, readily penetrating the skin when applied as a cream and abolishing lysyl oxidase activity. In murine models of injury and fibrosis, topical application reduces collagen deposition and cross-linking. Topical application of PXS-6302 after injury also significantly improves scar appearance without reducing tissue strength in porcine injury models. PXS-6302 therefore represents a promising therapeutic to ameliorate scar formation, with potentially broader applications in other fibrotic diseases.

Scars are a significant problem caused by excess collagen in the skin. Here the authors develop a topical drug that reduces collagen stability and leads to improved scar appearance and stiffness in preclinical models.

Details

Title
Topical application of an irreversible small molecule inhibitor of lysyl oxidases ameliorates skin scarring and fibrosis
Author
Chaudhari, Nutan 1 ; Findlay, Alison D. 2 ; Stevenson, Andrew W. 3   VIAFID ORCID Logo  ; Clemons, Tristan D. 4 ; Yao, Yimin 2 ; Joshi, Amar 2 ; Sayyar, Sepidar 5 ; Wallace, Gordon 5   VIAFID ORCID Logo  ; Rea, Suzanne 6 ; Toshniwal, Priyanka 3 ; Deng, Zhenjun 3 ; Melton, Philip E. 7 ; Hortin, Nicole 3 ; Iyer, K. Swaminathan 8 ; Jarolimek, Wolfgang 2 ; Wood, Fiona M. 9 ; Fear, Mark W. 3   VIAFID ORCID Logo 

1  The University of Western Australia, Burn Injury Research Unit, School of Biomedical Sciences, Crawley, Australia (GRID:grid.1012.2) (ISNI:0000 0004 1936 7910); The University of Western Australia, School of Molecular Sciences, Crawley, Australia (GRID:grid.1012.2) (ISNI:0000 0004 1936 7910) 
2  Pharmaxis Ltd, Drug Discovery Department, Sydney, Australia (GRID:grid.430252.2) 
3  The University of Western Australia, Burn Injury Research Unit, School of Biomedical Sciences, Crawley, Australia (GRID:grid.1012.2) (ISNI:0000 0004 1936 7910) 
4  The University of Western Australia, School of Molecular Sciences, Crawley, Australia (GRID:grid.1012.2) (ISNI:0000 0004 1936 7910); University of Southern Mississippi, School of Polymer Science and Engineering, Hattiesburg, USA (GRID:grid.267193.8) (ISNI:0000 0001 2295 628X) 
5  University of Wollongong, Intelligent Polymer Research Institute, Australian Research Council Centre of Excellence for Electromaterials Science, Wollongong, Australia (GRID:grid.1007.6) (ISNI:0000 0004 0486 528X); University of Wollongong, Australian National Fabrication Facility—Materials Node, Innovation Campus, Wollongong, Australia (GRID:grid.1007.6) (ISNI:0000 0004 0486 528X) 
6  Burns Service of Western Australia, WA, Department of Health, Nedlands, Australia (GRID:grid.413880.6) (ISNI:0000 0004 0453 2856) 
7  University of Tasmania, Menzies Institute for Medical Research, Hobart, Australia (GRID:grid.1009.8) (ISNI:0000 0004 1936 826X); Curtin University, School of Pharmacy and Biomedical Sciences, Bentley, Australia (GRID:grid.1032.0) (ISNI:0000 0004 0375 4078); University of Western Australia, School of Global Population Health, Crawley, Australia (GRID:grid.1012.2) (ISNI:0000 0004 1936 7910) 
8  The University of Western Australia, School of Molecular Sciences, Crawley, Australia (GRID:grid.1012.2) (ISNI:0000 0004 1936 7910) 
9  The University of Western Australia, Burn Injury Research Unit, School of Biomedical Sciences, Crawley, Australia (GRID:grid.1012.2) (ISNI:0000 0004 1936 7910); Burns Service of Western Australia, WA, Department of Health, Nedlands, Australia (GRID:grid.413880.6) (ISNI:0000 0004 0453 2856) 
Pages
5555
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-022-33148-5
ProQuest document ID
2716792120
Copyright
© The Author(s) 2022. corrected publication 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.