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NHS\u2010activated acrylamides allow for a fast functionalization of <jats:italic>N<\/jats:italic>\u2010terminal cysteines (<jats:italic>k<\/jats:italic><jats:sub>2<\/jats:sub>=1.54\u00b10.18\u00d710<jats:sup>3<\/jats:sup>\u2005M<jats:sup>\u22121<\/jats:sup>\u2009s<jats:sup>\u22121<\/jats:sup>) under dilute aqueous conditions, enabling selectivity over other nucleophilic amino acids. Additionally, the versatility of these new bioconjugation handles was demonstrated in the cross\u2010linking of in\u2010chain or <jats:italic>C<\/jats:italic>\u2010terminal cysteines with nearby lysine residues. NHS\u2010activated acrylamides are compatible with the use of other cysteine selective reagents, allowing for orthogonal dual\u2010modifications. This strategy was successfully applied to the late\u2010stage functionalization of peptides and proteins with a PEG unit, fluorescent probe, and cytotoxic agent. The level of molecular control offered by NHS\u2010activated acrylamides is expected to promote amino\u2010sulfhydryl stapling technology as a powerful strategy to design functional bioconjugates.<\/jats:p>","DOI":"10.1002\/ange.202016936","type":"journal-article","created":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T18:36:41Z","timestamp":1611945401000},"page":"10945-10952","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Efficient Amino\u2010Sulfhydryl Stapling on Peptides and Proteins Using Bifunctional NHS\u2010Activated Acrylamides"],"prefix":"10.1002","volume":"133","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4178-1942","authenticated-orcid":false,"given":"Maria J. S. 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