Cover Picture: Identification of Pharmacological Chaperones for Gaucher Disease and Characterization of Their Effects on β-Glucocerebrosidase by Hydrogen/Deuterium Exchange Mass Spectrometry (ChemBioChem 16/2008) (page 2549)
Michael B. Tropak, Gregory J. Kornhaber, Brigitte A. Rigat, Gustavo H. Maegawa, Justin D. Buttner, Jan E. Blanchard, Cecilia Murphy, Steven J. Tuske, Stephen J. Coales, Yoshitomo Hamuro, Eric D. Brown and Don J. Mahuran
Version of Record online: 29 OCT 2008 | DOI: 10.1002/cbic.200890061
The cover picture shows the regions (shades of blue) on human lysosomal glucocerebrosidase (green) that undergo a significant reduction in hydrogen–deuterium exchange (denoted by loss of blurriness) upon binding a 2,4-diamino-5-substituted quinazoline (MWP; red). MWP was identified in a high-throughput screen of the Maybridge library of 50 000 small molecule drug-like compounds (grey structures) for inhibitors. The confocal images immediately below the 3D structures of the enzyme are patient fibrobroblasts homozygous for the common N370S Gaucher disease type I allele, stained with an antibody against glucocerebrosidase (green); these show increased levels of the enzyme in MWP treated (+MWP) cells in comparison with untreated control (−MWP) cells. This study has identified pharmacological chaperones (PC) that are not based on the structure of the glycolipid substrate of the enzyme. These new compounds increase the repertoire of chemical frameworks available for the construction of efficient PCs for the treatment of Gaucher disease. For more details, see the article by M. B. Tropak, D. J. Mahuran et al. on p. 2650 ff.