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Enzyme inhibitors such as isofagomine, acting as pharmacological chaperones (PCs), increase these levels by binding and stabilizing the native form of the enzyme in the endoplasmic reticulum (ER), and allow increased lysosomal transport of the enzyme. A high\u2010throughput screen of the 50\u2009000\u2010compound Maybridge library identified two, non\u2010carbohydrate\u2010based inhibitory molecules, a 2,4\u2010diamino\u20105\u2010substituted quinazoline (IC<jats:sub>50<\/jats:sub> 5<jats:italic> \u03bc<jats:sc>M<\/jats:sc><\/jats:italic>) and a 5\u2010substituted pyridinyl\u20102\u2010furamide (IC<jats:sub>50<\/jats:sub> 8 \u03bc<jats:sc>M<\/jats:sc>). They raised the levels of functional GCase 1.5\u20132.5\u2010fold in N370S or F213I GD fibroblasts. Immunofluorescence confirmed that treated GD fibroblasts had decreased levels of GCase in their ER and increased levels in lysosomes. Changes in protein dynamics, monitored by hydrogen\/deuterium\u2010exchange mass spectrometry, identified a domain III active\u2010site loop (residues 243\u2013249) as being significantly stabilized upon binding of isofagomine or either of these two new compounds; this suggests a common mechanism for PC enhancement of intracellular transport.<\/jats:p>","DOI":"10.1002\/cbic.200800304","type":"journal-article","created":{"date-parts":[[2008,10,29]],"date-time":"2008-10-29T05:22:06Z","timestamp":1225257726000},"page":"2650-2662","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Identification of Pharmacological Chaperones for Gaucher Disease and Characterization of Their Effects on \u03b2\u2010Glucocerebrosidase by Hydrogen\/Deuterium Exchange Mass Spectrometry"],"prefix":"10.1002","volume":"9","author":[{"given":"Michael 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