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Here we report an efficient method for the synthesis of RNA–peptide conjugates by inverse-electron demand Diels–Alder reaction. Various dienophiles were enzymatically incorporated into RNA and reacted with a chemically synthesized diene-modified peptide. The Diels–Alder reaction proceeds with near-quantitative yields in aqueous solution with stoichiometric amounts of reactants, even at low micromolar concentrations.

Graphical abstract: RNA–peptide conjugate synthesis by inverse-electron demand Diels–Alder reaction

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