Science 350, 674–677 (2015)

Credit: SCIENCE

A hallmark of eye lens cataracts is the presence of aggregated crystallin proteins, a class of molecular chaperone that helps maintain the solubility of other lens proteins. To identify small-molecule chaperones, Makley et al. screened a ∼2,450-member compound library for those that that could inhibit the formation of the disease-linked crystallin amyloid. Potential candidates showed a decrease in the apparent melting transition temperature of the crystallin domain–containing protein Hsp27 on differential scanning fluorimetry. Over one-third of the confirmed active compounds were sterols, which led the authors ultimately to focus on 5-cholesten-3b,25-diol (compound 29) as their lead compound. NMR and in silico docking experiments suggested that compound 29 contacts both subunits of one of the cataract-related crystallin proteins, cryAB, to potentially stabilize its native state. Compound 29 could suppress amyloid formation, reverse the insolubility of the cataract-linked R120G cryAB mutant and partially disaggregate pre-formed amyloid. Compound 29 also improved lens transparency in two mouse models of hereditary cataract and in ex vivo–treated lens material from human patients with cataracts, increasing the amount of total soluble protein in both mouse tissue and human samples. These results suggest a new approach to cataract treatment using pharmacological chaperones.