2. Academic Validation
  3. Structure guided drug design to develop kallikrein 5 inhibitors to treat Netherton syndrome

Structure guided drug design to develop kallikrein 5 inhibitors to treat Netherton syndrome

  • Bioorg Med Chem Lett. 2019 Jun 15;29(12):1454-1458. doi: 10.1016/j.bmcl.2019.04.022.
Ann L Walker 1,  Ryan P Bingham 2,  Emma V Edgar 2,  Alan Ferrie 2,  Duncan S Holmes 2,  John Liddle 2,  Oxana Polyakova 2,  Monika Rella 2,  Kathrine J Smith 2,  James H Thorpe 2,  Yichen Wang 3,  Gemma V White 2,  Robert J Young 2,  Alain Hovnanian 3
Affiliations

Affiliations

  • 1 GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Electronic address: [email protected].
  • 2 GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
  • 3 INSERM UMR1163 Laboratory of Genetic Skin Diseases, Imagine Institute and Université Paris Descarte - Sorbonne Paris Cité, Paris, France.
PMID: 31005442 DOI: 10.1016/j.bmcl.2019.04.022
Abstract

The connection between Netherton syndrome and overactivation of epidermal/dermal proteases particularly KLK5 has been well established. To treat sufferers of this severe condition we wished to develop a topical KLK5 inhibitor in order to normalise epidermal shedding and reduce the associated inflammation and itching. In this paper we describe structure-based optimisation of a series of brightly coloured weak KLK5 inhibitors into colourless, non-irritant molecules with good KLK5 activity and selectivity over a range of serine proteases.

Keywords

KLK1; KLK5; KLKB1; LEKTI; Netherton syndrome; SPINK5.

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