Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 50, Issue 22, Pages 5357-5363Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm070687z
Keywords
-
Categories
Funding
- Medical Research Council [G0500306] Funding Source: Medline
- NIDDK NIH HHS [R01 DK075322, 1R01DK075322, 1R01DK064232, R01 DK064232] Funding Source: Medline
- NIGMS NIH HHS [5R01GM071872, R01 GM074832-02, R01 GM074832-01A1, R01 GM071872-02, R01 GM071872-03, R01 GM074832, 1R01GM074832, R01 GM071872, R01 GM071872-01] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
- MRC [G0500306] Funding Source: UKRI
- Medical Research Council [G0500306] Funding Source: researchfish
Ask authors/readers for more resources
The Z mutant of (xi-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 polymerization for rational structure-based 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. Modeling the effects of ligand binding on the cavity and re-screening the library identified an additional 10 compounds that completely blocked polymerization. The best antagonists were effective at ratios of compound to Z alpha(1)-antitrypsin of 2.5:1 and reduced the intracellular accumulation of Z a,-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 alpha-1-antitrypsin.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available