Bioorthogonal chemistries enable the study of diverse metabolites in living systems. Despite the sizable collection of bioorthogonal reagents now available, many still suffer from slow rates and poor intracellular stability. In addition, the majority of bioorthogonal ligations developed to date cannot be used simultaneously, precluding their use in multicomponent labeling applications. To fill this void, we are developing transformations that exploit unique mechanisms that can be employed in tandem. Included in this group are cyclopropene (Cp) cycloadditions with tetrazines, cyclopropenone (Cpo) ligations with phosphines, and 1,2,4-triazine cycloadditions with strained π-systems. To demonstrate their compatibilities, we first characterized the stability and rates of the individual reactions in aqueous solution. We further verified that the reactions are mutually orthogonal at the small molecule level. Last, we applied these reactions in model protein labeling experiments to showcase their mutual orthogonality under biologically relevant conditions. Collectively, our results imply that reactions with Cps, Cpos, and 1,2,4-triazines are mutually compatible, and are suitable for tracking multiple metabolites in concert.<br/>

Compatible bioorthogonal reactions for multicomponent labeling

255th National Meeting (2018)

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