Small Molecules Block the Polymerization of Z α₁-Antitrypsin and Increase the Clearance of Intracellular Aggregates

Abstract

The Z mutant of α 1 -antitrypsin (Glu342Lys) causes a domain-swap and the formation of intrahepatic polymers that aggregate as inclusions and predispose the homozygote to cirrhosis. We have identified an allosteric cavity that is distinct from the interface involved in polymerisation for rational structurebased drug design to block polymer formation. Virtual ligand screening was performed on 1.2 million small molecules and 6 compounds were identified that reduced polymer formation in vitro. Modelling the effects of ligand binding on the cavity and re-screening the library identified an additional 10 compounds that completely blocked polymerisation. The best antagonists were effective at ratios of compound to Z α 1 -antitrypsin of 2.5:1 and reduced the intracellular accumulation of Z α 1 -antitrypsin by 70% in a cell model of disease. Identifying small molecules provides a novel therapy for the treatment of liver disease associated with the Z allele of α 1 -antitrypsin.

Update on alpha-1 antitrypsin deficiency: New therapies

“…The and increased the secretion of Z α 1 -antitrypsin from a Xenopus oocyte expression system [46,90]. This cavity was used as a target for rational structure-based drug design to block polymer formation [91]. …”

Polymerization and Oxidation of Alpha-1-Antitrypsin in Pathogenesis of Emphysema

“…This approach could potentially ameliorate the liver disease, and defend respiratory epithelial surface, providing antielastase protection and avoiding the proinflammatory effects of polymerized Z A1AT. Currently, there is some progress in development of synthetic peptide designed to selectively inhibit Z polymerisation Parfrey et al, 2004;Chang et al, 2006;Mallya et al, 2007;Chang et al, 2009). …”

Recent Advances in the Research and Development of Alpha-1 Proteinase Inhibitor for Therapeutic Use

“…Mainly this approach has been explored with respect to the peptides and small molecules in order to prevent the aggregation of Z mutant (e.g., Mallya et al, 2007;Chang et al 2009). In the meantime, the protein's potential for binding small ligands of pharmaceutical interest has been proposed as a promising approach that is directed at, and may ultimately enhance, currently existing 1 −PI therapies (Karnaukhova et al, 2010).…”

“…Due to the abundance of 1 −PI in human plasma and its conservative tertiary structure with hydrophobic cavities (Elliott et al, 2000;Lee et al, 2001;Parfrey et al, 2003), 1 −PI has the capacity to bind small hydrophobic molecules. This property has been explored mainly with respect to the peptides and small molecules that may prevent the aggregation of the 1 −PI Z mutant (Mahadeva et al 2002;Mallya et al, 2007;Chang et al 2009). …”