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Pharmacological chaperones (PCs) which stabilize mutant GCase have been used to increase lysosomal activity through improving trafficking efficiency. By engineering their inherent basicity, we have synthesized PCs that change conformation between the ER and the lysosomal environment, thus weakening binding to GCase after its successful trafficking to the lysosome. NMR studies confirmed the conformational change while X\u2010ray data reveal bound conformations and binding modes. These results were further corroborated by cell studies showing increases in GCase activity when using the pH\u2010switchable probe at low dosing. Preliminary in vivo assays with humanized mouse models of Gaucher showed enhanced GCase activity levels in relevant tissues, including the brain, further supporting their potential.<\/jats:p>","DOI":"10.1002\/anie.202207974","type":"journal-article","created":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T02:08:14Z","timestamp":1658455694000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Pharmacological Chaperones for GCase that Switch Conformation with pH Enhance Enzyme Levels in Gaucher Animal Models"],"prefix":"10.1002","volume":"61","author":[{"given":"Andr\u00e9s G.","family":"Santana","sequence":"first","affiliation":[{"name":"Dept. of Chemistry University of British Columbia  Vancouver BC, V6T 1Z1 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyle","family":"Robinson","sequence":"additional","affiliation":[{"name":"Dept. of Chemistry University of British Columbia  Vancouver BC, V6T 1Z1 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chelsea","family":"Vickers","sequence":"additional","affiliation":[{"name":"Dept. of Biochemistry and Microbiology University of Victoria  Victoria BC, V8W 3P6 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew C.","family":"Deen","sequence":"additional","affiliation":[{"name":"Dept. of Chemistry and Dept. of Mol. 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