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

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

SUBMITTER: Lomas DA 

PROVIDER: S-EPMC7933930 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature