biostudies-literatureKataki-Anastasakou ANational Institute of General Medical SciencesNIGMS NIH HHS2124-2129https://www.ebi.ac.uk/biostudies/studies/S-EPMC9527085biostudies-literatureUnknown16(11)The widespread adoption of the bioorthogonal chemical reporter strategy revolutionized chemical biology. However, its translation to living mammals has been challenging, due to the size/stability properties of the chemical reporter group and/or the reaction kinetics of the labeling step. While developing new bioorthogonal reactions has been the traditional approach to optimizing the bioorthogonal chemical reporter strategy, here we present a different avenue, leveraging intermolecular interactions, to create bioorthogonal host-guest pairs. This approach, deemed "bioorthogonal complexation, does not rely on activated functional groups or second-order rate constants. We utilize the cucurbit[7]uril (CB[7]) scaffold to showcase bioorthogonal complexation and determine that medium-affinity (<i>ACS chemical biologyCell-surface Labeling via Bioorthogonal Host-Guest Chemistry.PMC95270851DP2GM13268DP2 GM132680R25 GM055052Sletten EMKataki-Anastasakou AHernandez SfalseCell-surface Labeling via Bioorthogonal Host-Guest Chemistry.The widespread adoption of the bioorthogonal chemical reporter strategy revolutionized chemical biology. However, its translation to living mammals has been challenging, due to the size/stability properties of the chemical reporter group and/or the reaction kinetics of the labeling step. While developing new bioorthogonal reactions has been the traditional approach to optimizing the bioorthogonal chemical reporter strategy, here we present a different avenue, leveraging intermolecular interactions, to create bioorthogonal host-guest pairs. This approach, deemed "bioorthogonal complexation, does not rely on activated functional groups or second-order rate constants. We utilize the cucurbit[7]uril (CB[7]) scaffold to showcase bioorthogonal complexation and determine that medium-affinity (<i>2021-01-01T00:00:00Z2021 Nov2025-04-22T19:06:09.649Z2025-04-06T02:38:19.279ZS-EPMC95270853466936710.1021/acschembio.1c00494