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The development of highly potent and selective small molecule correctors of Z α1-antitrypsin misfolding

DOI: 10.1016/j.bmcl.2021.127973 DOI Help

Authors: John Liddle (GlaxoSmithKline) , Andrew C. Pearce (GlaxoSmithKline) , Christopher Arico-Muendel (GlaxoSmithKline) , Svetlana Belyanskaya (GlaxoSmithKline) , Andrew Brewster (GlaxoSmithKline) , Murray Brown (GlaxoSmithKline) , Chun-Wa Chung (GlaxoSmithKline) , Alexis Denis (GlaxoSmithKline) , Nerina Dodic (GlaxoSmithKline) , Anthony Dossang (GlaxoSmithKline) , Peter Eddershaw (GlaxoSmithKline) , Diana Klimaszewska (GlaxoSmithKline) , Imran Haq (University College London) , Duncan S. Holmes (GlaxoSmithKline) , Alistair Jagger (University College London) , Toral Jakhria (GlaxoSmithKline) , Emilie Jigorel (GlaxoSmithKline) , Ken Lind (GlaxoSmithKline) , Jeff Messer (GlaxoSmithKline) , Margaret Neu (GlaxoSmithKline) , Allison Olszewski (GlaxoSmithKline) , Riccardo Ronzoni (University College London) , James Rowedder (GlaxoSmithKline) , Martin Rüdiger (GlaxoSmithKline) , Steve Skinner (GlaxoSmithKline) , Kathrine J. Smith (GlaxoSmithKline) , Lionel Trottet (GlaxoSmithKline) , Iain Uings (GlaxoSmithKline) , Zhengrong Zhu (GlaxoSmithKline) , James A. Irving (University College London) , David A. Lomas (University College London)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters , VOL 41

State: Published (Approved)
Published: June 2021
Diamond Proposal Number(s): 23853 , 17201

Abstract: α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z α1-antitrypsin were identified via a DNA-encoded library screen. A subsequent structure based optimisation led to a series of highly potent, selective and cellular active α1-antitrypsin correctors.

Journal Keywords: α1-Antitrypsin; Misfolding; 2-Oxindole

Diamond Keywords: Liver Disease

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


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)