A Potent and Selective Kallikrein-5 Inhibitor Delivers High Pharmacological Activity in Skin from Patients with Netherton Syndrome.

Autor:	Liddle J; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Beneton V; GlaxoSmithKline, Paris, France., Benson M; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Bingham R; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Bouillot A; GlaxoSmithKline, Paris, France., Boullay AB; GlaxoSmithKline, Paris, France., Brook E; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Cryan J; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Denis A; GlaxoSmithKline, Paris, France., Edgar E; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Ferrie A; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Fouchet MH; GlaxoSmithKline, Paris, France., Grillot D; GlaxoSmithKline, Paris, France., Holmes DS; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Howes A; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Krysa G; GlaxoSmithKline, Paris, France., Laroze A; GlaxoSmithKline, Paris, France., Lennon M; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., McClure F; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Moquette A; GlaxoSmithKline, Paris, France., Nicodeme E; GlaxoSmithKline, Paris, France., Santiago B; Discovery and Preclinical Development, GSK Dermatology Unit, Collegeville, Pennsylvania, USA., Santos L; Discovery and Preclinical Development, GSK Dermatology Unit, Collegeville, Pennsylvania, USA., Smith KJ; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Thorpe JH; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Thripp G; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Trottet L; GlaxoSmithKline, Paris, France., Walker AL; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Ward SA; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Wang Y; Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France., Wilson S; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Pearce AC; Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, United Kingdom., Hovnanian A; Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France; University of Paris, Paris, France; Department of Genetics, Necker hospital for sick children, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address: alain.hovnanian@inserm.fr.
Jazyk:	angličtina
Zdroj:	The Journal of investigative dermatology [J Invest Dermatol] 2021 Sep; Vol. 141 (9), pp. 2272-2279. Date of Electronic Publication: 2021 Mar 18.
DOI:	10.1016/j.jid.2021.01.029
Abstrakt:	Regulation of proteolytic activity in the skin plays a pivotal role in epidermal homeostasis. This is best exemplified in Netherton syndrome, a severe genetic skin condition caused by loss-of-function mutations in the gene serine protease inhibitor Kazal-type 5 encoding lympho-epithelial Kazal-type-related inhibitor, a serine protease inhibitor that regulates kallikrein (KLK)-related peptidase 5, 7, and 14 activities. KLK5 plays a central role in stratum corneum shedding and inflammatory cell signaling, activates KLK7 and KLK14, and is therefore an optimal therapeutic target. We aimed to identify a potent and selective small-molecule inhibitor of KLK5 amenable to epidermal delivery. GSK951 was identified using a structure-based design strategy and showed a half maximal inhibitory concentration of 250 pM for KLK5 and greater than 100-fold selectivity over KLK7 and KLK14. Cocrystal structure analysis identified the critical catalytic site interactions to a surrogate for KLK5. Topical application of GSK951-containing cream inhibited KLK5 activity in TgKLK5 mouse skin, reduced transepidermal water loss, and decreased proinflammatory cytokine expression. GSK951 achieved high concentrations in healthy human epidermis following topical application in a cream formulation. Finally, KLK5 protease activity was increased in stratum corneum of patients with Netherton syndrome and significantly inhibited by GSK951. These findings unveil a KLK5-specific small-molecule inhibitor with a high therapeutic potential for patients with Netherton syndrome. (Copyright © 2021 GlaxoSmithKline. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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