The development of highly potent and selective small molecule correctors of Z α1-antitrypsin misfolding. (1st June 2021)

• Record Type: Journal Article
• Authors: Liddle, John; Pearce, Andrew C.; Arico-Muendel, Christopher; Belyanskaya, Svetlana; Brewster, Andrew; Brown, Murray; Chung, Chun-wa; Denis, Alexis; Dodic, Nerina; Dossang, Anthony; Eddershaw, Peter; Klimaszewska, Diana; Haq, Imran; Holmes, Duncan S.; Jagger, Alistair; Jakhria, Toral; Jigorel, Emilie; Lind, Ken; Messer, Jeff; Neu, Margaret; Olszewski, Allison; Ronzoni, Riccardo; Rowedder, James; Rüdiger, Martin; Skinner, Steve; Smith, Kathrine J.; Trottet, Lionel; Uings, Iain; Zhu, Zhengrong; Irving, James A.; Lomas, David A.;
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 41(2021)
• Publication Date: 2021-06-01
• Subjects: α1-Antitrypsin -- Misfolding -- 2-Oxindole; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.127973
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z α1 -antitrypsin were identified via a DNA-encoded library screen. A subsequent structure based optimisation led to a series of highly potent, selective and cellular active α1-antitrypsin correctors.