Topical small molecule granzyme B inhibitor improves remodeling in a murine model of impaired burn wound healing

Experimental & Molecular Medicine
Yue ShenDavid J Granville

Abstract

Granzyme B (GzmB) is a serine protease that has long been thought to function exclusively in lymphocyte-mediated apoptosis. In recent years, this paradigm has been revisited due to the recognition that GzmB accumulates in the extracellular milieu in many autoimmune and chronic inflammatory disorders, and contributes to impaired tissue remodeling due to the cleavage of extracellular matrix proteins. Knockout studies suggest that GzmB-mediated cleavage of decorin (DCN) contributes to impaired collagen fibrillogenesis and remodeling. As DCN is anti-fibrotic and contributes to reduced hypertrophic scarring, GzmB-induced DCN cleavage could play a role in wound healing following burn injury. In the present study, a novel, gel-formulated, first-in-class small-molecule inhibitor of GzmB, VTI-1002, was assessed in a murine model of impaired, diabetic burn wound healing. VTI-1002 exhibited high specificity, potency, and target selectivity. Gel-formulated VTI-1002 was able to penetrate the stratum corneum and was retained in the skin with minimal systemic absorption. Daily topical administration of VTI-1002 gel for 30 days following thermal injury showed significantly accelerated wound closure, increased DCN protein levels, and collagen o...Continue Reading

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Citations

Oct 9, 2019·Journal of Clinical Medicine·Liqiang ZhangAlexandra R Lucas
Aug 29, 2019·Expert Opinion on Therapeutic Targets·Christopher T TurnerDavid J Granville
Jul 13, 2019·Frontiers in Immunology·Sho HiroyasuDavid J Granville
Oct 27, 2018·International Journal of Molecular Sciences·James S LeeKiarash Khosrotehrani
Jan 14, 2021·Nature Communications·Sho HiroyasuDavid J Granville
Jun 7, 2020·The Journal of Investigative Dermatology·Christopher T TurnerDavid J Granville
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Apr 28, 2021·Journal of Medicinal Chemistry·Hong-Rae KimEuna Yoo
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Methods Mentioned

BETA
Assay

Software Mentioned

ImageJ
NumPy
GraphPad
Python
Image
GraphPad Prism

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