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Herein, we report a new method of <jats:italic>N<\/jats:italic>\u2010terminal cysteine modification using <jats:italic>O<\/jats:italic>\u2010salicylaldehyde esters (OSAEs) through fast conjugation and irreversible deconjugation. These reagents can rapidly react with <jats:italic>N<\/jats:italic>\u2010terminal Cys at low\u2010micromolar concentration to form thiazolidines with subsequent hydrolysis of the ester moiety to the phenolic derivative. These phenolic thiazolidines can be hydrolyzed at acidic pH (\u22484.5) to recover the intact <jats:italic>N<\/jats:italic>\u2010terminal Cys. Bioconjugation reactions using OSAEs offer controlled reversibility to as act as a protecting group for <jats:italic>N<\/jats:italic>\u2010terminal cysteines, allowing the modification of in\u2010chain residues without perturbing the <jats:italic>N<\/jats:italic>\u2010terminal Cys, which can then be deprotected and used as a conjugation site.<\/jats:p>","DOI":"10.1002\/chem.202202377","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T03:24:33Z","timestamp":1665977073000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Interactive Bioconjugation at <i>N<\/i>\u2010Terminal Cysteines by Using <i>O<\/i>\u2010Salicylaldehyde Esters towards Dual Site\u2010Selective Functionalization"],"prefix":"10.1002","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4178-1942","authenticated-orcid":false,"given":"Maria J. S. A.","family":"Silva","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy Universidade de Lisboa  Av. Prof. Gama Pinto 1649-003 Lisboa Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4252-6767","authenticated-orcid":false,"given":"Rafaela A. N.","family":"Cavadas","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy Universidade de Lisboa  Av. Prof. Gama Pinto 1649-003 Lisboa Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0378-3624","authenticated-orcid":false,"given":"H\u00e9lio","family":"Faustino","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy Universidade de Lisboa  Av. 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