EMBO Molecular Medicine (Mar 2021)
Development of a small molecule that corrects misfolding and increases secretion of Z α1‐antitrypsin
- David A Lomas,
- James A Irving,
- Christopher Arico‐Muendel,
- Svetlana Belyanskaya,
- Andrew Brewster,
- Murray Brown,
- Chun‐wa Chung,
- Hitesh Dave,
- Alexis Denis,
- Nerina Dodic,
- Anthony Dossang,
- Peter Eddershaw,
- Diana Klimaszewska,
- Imran Haq,
- Duncan S Holmes,
- Jonathan P Hutchinson,
- Alistair M Jagger,
- Toral Jakhria,
- Emilie Jigorel,
- John Liddle,
- Ken Lind,
- Stefan J Marciniak,
- Jeff Messer,
- Margaret Neu,
- Allison Olszewski,
- Adriana Ordonez,
- Riccardo Ronzoni,
- James Rowedder,
- Martin Rüdiger,
- Steve Skinner,
- Kathrine J Smith,
- Rebecca Terry,
- Lionel Trottet,
- Iain Uings,
- Steve Wilson,
- Zhengrong Zhu,
- Andrew C Pearce
Affiliations
- David A Lomas
- UCL Respiratory Rayne Institute University College London London UK
- James A Irving
- UCL Respiratory Rayne Institute University College London London UK
- Christopher Arico‐Muendel
- GlaxoSmithKline Cambridge MA USA
- Svetlana Belyanskaya
- GlaxoSmithKline Cambridge MA USA
- Andrew Brewster
- GlaxoSmithKline Stevenage UK
- Murray Brown
- GlaxoSmithKline Stevenage UK
- Chun‐wa Chung
- GlaxoSmithKline Stevenage UK
- Hitesh Dave
- GlaxoSmithKline Stevenage UK
- Alexis Denis
- GlaxoSmithKline Paris France
- Nerina Dodic
- GlaxoSmithKline Paris France
- Anthony Dossang
- GlaxoSmithKline Stevenage UK
- Peter Eddershaw
- GlaxoSmithKline Stevenage UK
- Diana Klimaszewska
- GlaxoSmithKline Stevenage UK
- Imran Haq
- UCL Respiratory Rayne Institute University College London London UK
- Duncan S Holmes
- GlaxoSmithKline Stevenage UK
- Jonathan P Hutchinson
- GlaxoSmithKline Stevenage UK
- Alistair M Jagger
- UCL Respiratory Rayne Institute University College London London UK
- Toral Jakhria
- GlaxoSmithKline Stevenage UK
- Emilie Jigorel
- GlaxoSmithKline Paris France
- John Liddle
- GlaxoSmithKline Stevenage UK
- Ken Lind
- GlaxoSmithKline Cambridge MA USA
- Stefan J Marciniak
- Cambridge Institute for Medical Research Cambridgem UK
- Jeff Messer
- GlaxoSmithKline Cambridge MA USA
- Margaret Neu
- GlaxoSmithKline Stevenage UK
- Allison Olszewski
- GlaxoSmithKline Cambridge MA USA
- Adriana Ordonez
- Cambridge Institute for Medical Research Cambridgem UK
- Riccardo Ronzoni
- UCL Respiratory Rayne Institute University College London London UK
- James Rowedder
- GlaxoSmithKline Stevenage UK
- Martin Rüdiger
- GlaxoSmithKline Stevenage UK
- Steve Skinner
- GlaxoSmithKline Cambridge MA USA
- Kathrine J Smith
- GlaxoSmithKline Stevenage UK
- Rebecca Terry
- GlaxoSmithKline Stevenage UK
- Lionel Trottet
- GlaxoSmithKline Paris France
- Iain Uings
- GlaxoSmithKline Stevenage UK
- Steve Wilson
- GlaxoSmithKline Stevenage UK
- Zhengrong Zhu
- GlaxoSmithKline Cambridge MA USA
- Andrew C Pearce
- GlaxoSmithKline Stevenage UK
- DOI
- https://doi.org/10.15252/emmm.202013167
- Journal volume & issue
-
Vol. 13,
no. 3
pp. n/a – n/a
Abstract
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.
Keywords