Development of a small molecule that corrects misfolding and increases secretion of Z α1‐antitrypsin

• Main Authors: 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
• Format: Article
• Language: English
• Published: Wiley 2021-03-01
• Series: EMBO Molecular Medicine
• Subjects: emphysema; liver disease; protein misfolding; small molecule corrector; α1‐antitrypsin deficiency
• Online Access: https://doi.org/10.15252/emmm.202013167
• ISSN: 1757-4676; 1757-4684

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.