John Liddle; Andrew C. Pearce; Christopher Arico-Muendel; Svetlana Belyanskaya; Andrew Brewster; Murray Brown; Chun-wa Chung; Alexis Denis; Nerina Dodic; Anthony Dossang; Peter Eddershaw; Diana Klimaszewska; Imran Haq; Duncan S. Holmes; Alistair Jagger; Toral Jakhria; Emilie Jigorel; Ken Lind; Jeff Messer; Margaret Neu; Allison Olszewski; Riccardo Ronzoni; James Rowedder; Martin Rüdiger; Steve Skinner; Kathrine J. Smith; Lionel Trottet; Iain Uings; Zhengrong Zhu; James A. Irving; David A. Lomas
Bioorg. Med. Chem. Lett., 2021, 127973
https://doi.org/10.1016/j.bmcl.2021.127973

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.