Peptido RNAs are hybrid molecules with a phosphoramidate link between the N‐terminus of a peptide and the 5'‐phosphate of an oligoribonucleotide. Such species are formed in spontaneous co‐oligomerizations of amino acids and ribonucleotides in aqueous condensation buffer. To shed light on the properties of these fascinating molecules, a synthetic method for their preparation in monodisperse form is needed. Herein, we report how peptido RNAs can be prepared via solution‐phase coupling of unprotected peptides and oligoribonucleotides in aqueous solution. The preferred protocol uses pre‐activation of the 5'‐phosphate of the RNA as an imidazolide at pH 6.5, followed by precipitation and coupling to the peptide at pH 8 with an organocatalyst. The procedure gave peptido RNAs from water‐soluble peptides and synthetic oligoribonucleotides in up to 68 % yield. The method is convenient and inexpensive and can produce NMR quantities, opening the door to the systematic exploration of the chemistry of peptido RNAs.
The Front Cover shows the structure of a peptido RNA that was prepared in NMR quantities from a peptide and an oligoribonucleotide in aqueous solution, without the need for protecting groups. The two‐step protocol starts with conversion of the 5'‐terminal phosphate of the RNA to an imidazolide, followed by 1‐ethylimidazole‐catalyzed coupling at pH 8 that produces the phosphoramidate‐linked final product. The method opens the door to the systematic investigation of molecular hybrids implicated in the origin of RNA‐directed protein synthesis. More information can be found in the Full Paper by C. Richert et al.
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