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

Lomas, DA; Irving, JA; Arico-Muendel, C; Belyanskaya, S; Brewster, A; Brown, M; Chung, C-W; ... Pearce, AC; + view all (2021) Development of a small molecule that corrects misfolding and increases secretion of Z α1 -antitrypsin. EMBO Molecular Medicine , Article e13167. 10.15252/emmm.202013167. (In press). Green open access

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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.

Type: Article
Title: Development of a small molecule that corrects misfolding and increases secretion of Z α1 -antitrypsin
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/emmm.202013167
Publisher version: https://doi.org/10.15252/emmm.202013167
Language: English
Additional information: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/
Keywords: emphysema, liver disease, protein misfolding, small molecule corrector, α1-antitrypsin deficiency
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
UCL > Provost and Vice Provost Offices > VP: Health
URI: https://discovery.ucl.ac.uk/id/eprint/10120676
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