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Development of a small molecule that corrects misfolding and increases secretion of Z α 1 ‐antitrypsin

DOI: 10.15252/emmm.202013167 DOI Help

Authors: David A. Lomas (University College London) , James A. Irving (University College London) , Christopher Arico‐muendel (GlaxoSmithKline) , Svetlana Belyanskaya (GlaxoSmithKline) , Andrew Brewster (GlaxoSmithKline) , Murray Brown (GlaxoSmithKline) , Chun‐wa Chung (GlaxoSmithKline) , Hitesh Dave (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) , Jonathan P. Hutchinson (GlaxoSmithKline) , Alistair M. Jagger (University College London) , Toral Jakhria (GlaxoSmithKline) , Emilie Jigorel (GlaxoSmithKline) , John Liddle (GlaxoSmithKline) , Ken Lind (GlaxoSmithKline) , Stefan J Marciniak (Cambridge Institute for Medical Research) , Jeff Messer (GlaxoSmithKline) , Margaret Neu (GlaxoSmithKline) , Allison Olszewski (GlaxoSmithKline) , Adriana Ordonez (Cambridge Institute for Medical Research) , Riccardo Ronzoni (University College London) , James Rowedder (GlaxoSmithKline) , Martin Rüdiger (GlaxoSmithKline) , Steve Skinner (GlaxoSmithKline) , Kathrine J. Smith (GlaxoSmithKline) , Rebecca Terry (GlaxoSmithKline) , Lionel Trottet (GlaxoSmithKline) , Iain Uings (GlaxoSmithKline) , Steve Wilson (GlaxoSmithKline) , Zhengrong Zhu (GlaxoSmithKline) , Andrew C. Pearce (GlaxoSmithKline)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Embo Molecular Medicine , VOL 13

State: Published (Approved)
Published: March 2021
Diamond Proposal Number(s): 23853

Open Access Open Access

Abstract: Severe α1‐antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1‐antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA‐encoded chemical library to undertake a high‐throughput screen to identify small molecules that bind to, and stabilise Z α1‐antitrypsin. The lead compound blocks Z α1‐antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α1‐antitrypsin threefold in an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1‐antitrypsin into the plasma by sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that “mutation ameliorating” small molecules can block the aberrant polymerisation that underlies Z α1‐antitrypsin deficiency.

Diamond Keywords: Lung Disease; Liver Disease

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

Instruments: I03-Macromolecular Crystallography

Added On: 10/03/2021 09:17


Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)