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 Sayar; 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

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

Research output: Contribution to journal › Article › peer-review

17 Citations (Scopus)

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.

Original language	English
Article number	5555
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33148-5
Publication status	Published - Dec 2022

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Chaudhari, N., Findlay, A. D., Stevenson, A. W., Clemons, T. D., Yao, Y., Joshi, A., Sayar, S., Wallace, G., Rea, S., Toshniwal, P., Deng, Z., Melton, P. E., Hortin, N., Iyer, K. S., Jarolimek, W., Wood, F. M., & Fear, M. W. (2022). Topical application of an irreversible small molecule inhibitor of lysyl oxidases ameliorates skin scarring and fibrosis. Nature Communications, 13(1), Article 5555. https://doi.org/10.1038/s41467-022-33148-5

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title = "Topical application of an irreversible small molecule inhibitor of lysyl oxidases ameliorates skin scarring and fibrosis",

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.",

author = "Nutan Chaudhari and Findlay, {Alison D.} and Stevenson, {Andrew W.} and Clemons, {Tristan D.} and Yimin Yao and Amar Joshi and Sepidar Sayar and Gordon Wallace and Suzanne Rea and Priyanka Toshniwal and Zhenjun Deng and Melton, {Philip E.} and Nicole Hortin and Iyer, {K. Swaminathan} and Wolfgang Jarolimek and Wood, {Fiona M.} and Fear, {Mark W.}",

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doi = "10.1038/s41467-022-33148-5",

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Chaudhari, N, Findlay, AD, Stevenson, AW , Clemons, TD, Yao, Y, Joshi, A, Sayar, S, Wallace, G, Rea, S, Toshniwal, P, Deng, Z, Melton, PE , Hortin, N, Iyer, KS, Jarolimek, W, Wood, FM & Fear, MW 2022, 'Topical application of an irreversible small molecule inhibitor of lysyl oxidases ameliorates skin scarring and fibrosis', Nature Communications, vol. 13, no. 1, 5555. https://doi.org/10.1038/s41467-022-33148-5

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AU - Chaudhari, Nutan

AU - Findlay, Alison D.

AU - Stevenson, Andrew W.

AU - Clemons, Tristan D.

AU - Yao, Yimin

AU - Joshi, Amar

AU - Sayar, Sepidar

AU - Wallace, Gordon

AU - Rea, Suzanne

AU - Toshniwal, Priyanka

AU - Deng, Zhenjun

AU - Melton, Philip E.

AU - Hortin, Nicole

AU - Iyer, K. Swaminathan

AU - Jarolimek, Wolfgang

AU - Wood, Fiona M.

AU - Fear, Mark W.

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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

Abstract

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Targeting collagen cross-linking to improve scar appearance

Assessing Efficacy of Polyfunctional Nanoparticles Engineered for the Delivery of Multiple Therapeutics in Reduction of Cardiac Ischemia Reperfusion Injury

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

Cite this

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

Abstract

Access to Document

Other files and links

Fingerprint

Projects

Targeting collagen cross-linking to improve scar appearance

Assessing Efficacy of Polyfunctional Nanoparticles Engineered for the Delivery of Multiple Therapeutics in Reduction of Cardiac Ischemia Reperfusion Injury

Research output

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

Cite this