Synthesis of Peptido RNAs from Unprotected Peptides and Oligoribonucleotides via Coupling in Aqueous Solution

Abstract

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.