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

被引：33

作者：

Lomas, David A. ^{[1
]}

Irving, James A. ^{[1
]}

Arico-Muendel, Christopher ^{[2
]}

Belyanskaya, Svetlana ^{[2
]}

Brewster, Andrew ^{[3
]}

Brown, Murray ^{[3
]}

Chung, Chun-wa ^{[3
]}

Dave, Hitesh ^{[3
]}

Denis, Alexis ^{[4
]}

Dodic, Nerina ^{[4
]}

Dossang, Anthony ^{[3
]}

Eddershaw, Peter ^{[3
]}

Klimaszewska, Diana ^{[3
]}

Haq, Imran ^{[1
]}

Holmes, Duncan S. ^{[3
]}

Hutchinson, Jonathan P. ^{[3
]}

Jagger, Alistair M. ^{[1
]}

Jakhria, Toral ^{[3
]}

Jigorel, Emilie ^{[4
]}

Liddle, John ^{[3
]}

Lind, Ken ^{[2
]}

Marciniak, Stefan J. ^{[5
]}

Messer, Jeff ^{[2
]}

Neu, Margaret ^{[3
]}

Olszewski, Allison ^{[2
]}

Ordonez, Adriana ^{[5
]}

Ronzoni, Riccardo ^{[1
]}

Rowedder, James ^{[3
]}

Ruediger, Martin ^{[3
]}

Skinner, Steve ^{[2
]}

Smith, Kathrine J. ^{[3
]}

Terry, Rebecca ^{[3
]}

Trottet, Lionel ^{[4
]}

Uings, Iain ^{[3
]}

Wilson, Steve ^{[3
]}

Zhu, Zhengrong ^{[2
]}

Pearce, Andrew C. ^{[3
]}

机构：

[1] UCL, Rayne Inst, UCL Resp, London, England

[2] GlaxoSmithKline, Cambridge, MA USA

[3] GlaxoSmithKline, Stevenage, Herts, England

[4] GlaxoSmithKline, Paris, France

[5] Cambridge Inst Med Res, Cambridgem, England

来源：

EMBO MOLECULAR MEDICINE | 2021年 / 13卷 / 03期

基金：

英国医学研究理事会; 英国生物技术与生命科学研究理事会;

关键词：

emphysema; liver disease; protein misfolding; small molecule corrector; alpha(1)-antitrypsin deficiency;

D O I：

10.15252/emmm.202013167

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Severe alpha(1)-antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant alpha(1)-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 alpha(1)-antitrypsin. The lead compound blocks Z alpha(1)-antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z alpha(1)-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 alpha(1)-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 alpha(1)-antitrypsin deficiency.

引用

页数：16

共 47 条

[11] Antisense oligonucleotide treatment ameliorates alpha-1 antitrypsin-related liver disease in mice [J].