Enzyme Mechanism Study Reveals Drug Lead For Rare Disease

A mechanistic study of enzyme mutations that cause a rare disease has led to the discovery of a potential therapy. Cornelia de Lange Syndrome (CdLS) is a congenital condition that affects some one in 10,000 newborns. It is characterized by intellectual disability, facial abnormalities, and limb deformities. A collaborative team recently found that mutations in the metalloenzyme histone deacetylase 8 (HDAC8) cause about 4% of CdLS cases. David W. Christianson of the University of Pennsylvania and coworkers have now used crystallography and other techniques to show how the compromised structure, function, and stability of HDAC8 mutants can cause CdLS (ACS Chem. Biol. 2014, DOI: 10.1021/cb5003762). They also found that the catalytic activity of the mutant enzymes can be partially restored by a small-molecule activator, N-(phenylcarbamothioyl)benzamide, thus pointing to the first potential therapeutic for CdLS. “While preexisting physical deformities would not be reversed by the administration of an HDAC8 activator, the rescue of catalysis could potentially attenuate development-related manifestations of CdLS, such as progressive neurocognitive impairment,” Christianson says.