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A Potent and Selective Kallikrein-5 Inhibitor Delivers High Pharmacological Activity in Skin from Patients with Netherton Syndrome.
Liddle, John; Beneton, Veronique; Benson, Matthew; Bingham, Ryan; Bouillot, Anne; Boullay, Anne-Benedicte; Brook, Eloisa; Cryan, Jenni; Denis, Alexis; Edgar, Emma; Ferrie, Alan; Fouchet, Marie-Helene; Grillot, Didier; Holmes, Duncan S; Howes, Ashleigh; Krysa, Gael; Laroze, Alain; Lennon, Mark; McClure, Fiona; Moquette, Alexandre; Nicodeme, Edwige; Santiago, Brandon; Santos, Leandro; Smith, Kathrine J; Thorpe, James H; Thripp, Gary; Trottet, Lionel; Walker, Ann L; Ward, Simon A; Wang, Yichen; Wilson, Steve; Pearce, Andrew C; Hovnanian, Alain.
Afiliación
  • 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
J Invest Dermatol ; 141(9): 2272-2279, 2021 09.
Article en En | MEDLINE | ID: mdl-33744298
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piel / Compuestos de Boro / Calicreínas / Síndrome de Netherton / Inflamación / Antiinflamatorios Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Invest Dermatol Año: 2021 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piel / Compuestos de Boro / Calicreínas / Síndrome de Netherton / Inflamación / Antiinflamatorios Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Invest Dermatol Año: 2021 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos