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Nonenzymatic reactivity of 4\u2010chloropyridine with amino acids and thiols was ranked with respect to common covalent protein\u2010modifying reagents and found to have reactivity similar to that of acrylamide, but could be switched to a reactivity similar to that of iodoacetamide upon stabilization of the positively charged pyridinium. Diverse, fragment\u2010sized 4\u2010halopyridines inactivated human dimethylarginine dimethylaminohydrolase\u20101 (DDAH1) through covalent modification of the active site cysteine, acting as quiescent affinity labels that required off\u2010pathway catalysis through stabilization of the protonated pyridinium by a neighboring aspartate residue. A series of 2\u2010fluoromethyl\u2010substituted 4\u2010chloropyridines demonstrated that the p<jats:italic>K<\/jats:italic><jats:sub>a<\/jats:sub> and <jats:italic>k<\/jats:italic><jats:sub>inact<\/jats:sub>\/<jats:italic>K<\/jats:italic><jats:sub>I<\/jats:sub> values could be predictably varied over several orders of magnitude. Covalent labeling of proteins in an <jats:italic>Escherichia coli<\/jats:italic> lysate was shown to require folded proteins, indicating that alternative proteins can be targeted, and modification is likely to be catalysisdependent. 4\u2010Halopyridines, and quiescent affinity labels in general, represent an attractive strategy to develop reagents with switchable electrophilicity as selective covalent protein modifiers.<\/jats:p>","DOI":"10.1002\/cbic.201700104","type":"journal-article","created":{"date-parts":[[2017,5,3]],"date-time":"2017-05-03T22:22:55Z","timestamp":1493850175000},"page":"1551-1556","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Selective Covalent Protein Modification by 4\u2010Halopyridines through Catalysis"],"prefix":"10.1002","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4563-0025","authenticated-orcid":false,"given":"Christopher L.","family":"Schardon","sequence":"first","affiliation":[{"name":"Biochemistry Graduate Program The University of Texas  Austin TX 78712 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfred","family":"Tuley","sequence":"additional","affiliation":[{"name":"Division of Chemical Biology and Medicinal Chemistry College of Pharmacy The University of Texas  Austin TX 78712 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joyce A. 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