Topical application of an irreversible small molecule inhibitor of lysyl oxidases ameliorates skin scarring and fibrosis

Nutan Chaudhari; Alison D Findlay; Andrew W Stevenson; Tristan D Clemons; Yimin Yao; Amar Joshi; Sepidar Sayyar; Gordon Wallace; Suzanne Rea; Priyanka Toshniwal; Zhenjun Deng; Philip E Melton; Nicole Hortin; K Swaminathan Iyer; Wolfgang Jarolimek; Fiona M Wood; Mark W Fear

doi:10.1038/s41467-022-33148-5

Topical application of an irreversible small molecule inhibitor of lysyl oxidases ameliorates skin scarring and fibrosis

Nat Commun. 2022 Sep 22;13(1):5555. doi: 10.1038/s41467-022-33148-5.

Authors

Nutan Chaudhari^{1

2}, Alison D Findlay³, Andrew W Stevenson¹, Tristan D Clemons^{2

4}, Yimin Yao³, Amar Joshi³, Sepidar Sayyar^{5

6}, Gordon Wallace^{5

6}, Suzanne Rea⁷, Priyanka Toshniwal¹, Zhenjun Deng¹, Philip E Melton^{8

9

10}, Nicole Hortin¹, K Swaminathan Iyer², Wolfgang Jarolimek³, Fiona M Wood^{1

7}, Mark W Fear¹¹

Affiliations

¹ Burn Injury Research Unit, School of Biomedical Sciences, The University of Western Australia, Crawley, Australia.
² School of Molecular Sciences, The University of Western Australia, Crawley, Australia.
³ Drug Discovery Department, Pharmaxis Ltd, Sydney, NSW, Australia.
⁴ School of Polymer Science and Engineering, University of Southern Mississippi, Hattiesburg, MS, 39406, USA.
⁵ Intelligent Polymer Research Institute, Australian Research Council Centre of Excellence for Electromaterials Science, University of Wollongong, Wollongong, NSW, 2500, Australia.
⁶ Australian National Fabrication Facility-Materials Node, Innovation Campus, University of Wollongong, Wollongong, NSW, 2500, Australia.
⁷ Burns Service of Western Australia, WA, Department of Health, Nedlands, WA, Australia.
⁸ Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
⁹ School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, WA, Australia.
¹⁰ School of Global Population Health, University of Western Australia, Crawley, Australia.
¹¹ Burn Injury Research Unit, School of Biomedical Sciences, The University of Western Australia, Crawley, Australia. mark.fear@uwa.edu.au.

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.

Publication types

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

MeSH terms

Animals
Cicatrix* / drug therapy
Collagen
Fibrosis
Mice
Protein-Lysine 6-Oxidase*
Skin
Swine

Substances

Collagen
Protein-Lysine 6-Oxidase