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Evaluation of a crystallographic surrogate for kallikrein 5 in the discovery of novel inhibitors for Netherton syndrome

DOI: 10.1107/S2053230X19003169 DOI Help

Authors: James H. Thorpe (GlaxoSmithKline) , Emma V. Edgar (GlaxoSmithKline) , Kathrine J. Smith (GlaxoSmithKline) , Xiao Q. Lewell (GlaxoSmithKline) , Monika Rella (GlaxoSmithKline) , Gemma V. White (GlaxoSmithKline) , Oxana Polyakova (GlaxoSmithKline) , Pamela Nassau (GlaxoSmithKline) , Ann L. Walker (GlaxoSmithKline) , Duncan S. Holmes (GlaxoSmithKline) , Andrew C. Pearce (GlaxoSmithKline) , Yichen Wang (Imagine Institute; Université Paris Descartes–Sorbonne Paris Cité) , John Liddle (GlaxoSmithKline) , Alain Hovnanian (Imagine Institute; Université Paris Descartes–Sorbonne Paris Cité)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acta Crystallographica Section F Structural Biology Communications , VOL 75 , PAGES 385 - 391

State: Published (Approved)
Published: May 2019

Abstract: The inhibition of kallikrein 5 (KLK5) has been identified as a potential strategy for treatment of the genetic skin disorder Netherton syndrome, in which loss-of-function mutations in the SPINK5 gene lead to down-regulation of the endogenous inhibitor LEKTI-1 and profound skin-barrier defects with severe allergic manifestations. To aid in the development of a medicine for this target, an X-ray crystallographic system was developed to facilitate fragment-guided chemistry and knowledge-based drug-discovery approaches. Here, the development of a surrogate crystallographic system in place of KLK5, which proved to be challenging to crystallize, is described. The biochemical robustness of the crystallographic surrogate and the suitability of the system for the study of small nonpeptidic fragments and lead-like molecules are demonstrated.

Journal Keywords: Netherton syndrome; kallikrein; GSK144; structure-guided design; medicinal chemistry

Diamond Keywords: Netherton Syndrome

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 08/05/2019 11:02

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)