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Direct 3\u2010amino\u20102\u2010(trifluoromethyl)quinazolin\u20104(3<jats:italic>H<\/jats:italic>)\u2010one\u2010mediated aziridination of <jats:sc>l<\/jats:sc>\u2010<jats:italic>ido<\/jats:italic>\u2010configured cyclohexene has enabled the synthesis of new covalent inhibitors and ABPs of \u03b1\u2010<jats:sc>l<\/jats:sc>\u2010iduronidase, deficiency of which underlies the lysosomal storage disorder mucopolysaccharidosis type\u2005I (MPS\u2005I). The iduronidase ABPs react covalently and irreversibly in an activity\u2010based manner with human recombinant \u03b1\u2010<jats:sc>l<\/jats:sc>\u2010iduronidase (rIDUA, Aldurazyme<jats:sup>\u00ae<\/jats:sup>). The structures of IDUA when complexed with the inhibitors in a non\u2010covalent transition state mimicking form and a covalent enzyme\u2010bound form provide insights into its conformational itinerary. Inhibitors <jats:bold>1<\/jats:bold>\u2013<jats:bold>3<\/jats:bold> adopt a half\u2010chair conformation in solution (<jats:sup>4<\/jats:sup>H<jats:sub>3<\/jats:sub> and <jats:sup>3<\/jats:sup>H<jats:sub>4<\/jats:sub>), as predicted by DFT calculations, which is different from the conformation of the Michaelis complex observed by crystallographic studies. Consequently, <jats:bold>1<\/jats:bold>\u2013<jats:bold>3<\/jats:bold> may need to overcome an energy barrier in order to switch from the <jats:sup>4<\/jats:sup>H<jats:sub>3<\/jats:sub> conformation to the transition state (<jats:sup>2,\u20095<\/jats:sup>B) binding conformation before reacting and adopting a covalent <jats:sup>5<\/jats:sup>S<jats:sub>1<\/jats:sub> conformation. rIDUA can be labeled with fluorescent Cy5 ABP <jats:bold>2<\/jats:bold>, which allows monitoring of the delivery of therapeutic recombinant enzyme to lysosomes, as is intended in enzyme replacement therapy for the treatment of MPS\u2005I patients.<\/jats:p>","DOI":"10.1002\/chem.201804662","type":"journal-article","created":{"date-parts":[[2018,10,11]],"date-time":"2018-10-11T08:09:26Z","timestamp":1539245366000},"page":"19081-19088","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["New Irreversible \u03b1\u2010<scp>l<\/scp>\u2010Iduronidase Inhibitors and Activity\u2010Based Probes"],"prefix":"10.1002","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3051-3902","authenticated-orcid":false,"given":"Marta","family":"Artola","sequence":"first","affiliation":[{"name":"Department of Bio-organic Synthesis Leiden Institute of Chemistry Leiden University  Einsteinweg 55 2333 CC Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3748-5008","authenticated-orcid":false,"given":"Chi\u2010Lin","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry Leiden Institute of Chemistry Leiden University  Einsteinweg 55 2333 CC Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen A.","family":"McMahon","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Research Complex School of Biology University of St Andrews  North Haugh St Andrews Fife KY16 9ST UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Oehler","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Research Complex School of Biology University of St Andrews  North Haugh St Andrews Fife KY16 9ST UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6291-1569","authenticated-orcid":false,"given":"Thomas","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Bio-organic Synthesis Leiden Institute of Chemistry Leiden University  Einsteinweg 55 2333 CC Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn","family":"van\u2005der\u2005Lienden","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry Leiden Institute of Chemistry Leiden University  Einsteinweg 55 2333 CC Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"He","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Simon Fraser University  8888 University Drive Burnaby BC V5A 1S6 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"van\u2005den\u2005Elst","sequence":"additional","affiliation":[{"name":"Department of Bio-organic Synthesis Leiden Institute of Chemistry Leiden University  Einsteinweg 55 2333 CC Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogdan I.","family":"Florea","sequence":"additional","affiliation":[{"name":"Department of Bio-organic Synthesis Leiden Institute of Chemistry Leiden University  Einsteinweg 55 2333 CC Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison R.","family":"Kermode","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Simon Fraser University  8888 University Drive Burnaby BC V5A 1S6 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gijsbert A.","family":"van\u2005der\u2005Marel","sequence":"additional","affiliation":[{"name":"Department of Bio-organic Synthesis Leiden Institute of Chemistry Leiden University  Einsteinweg 55 2333 CC Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracey M.","family":"Gloster","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Research Complex School of Biology University of St Andrews  North Haugh St Andrews Fife KY16 9ST UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3531-2138","authenticated-orcid":false,"given":"Jeroen D. 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