Prolinyl Nucleotides Drive Enzyme‐Free Genetic Copying of RNA

Proline is one of the proteinogenic amino acids. It is found in all kingdoms of life. It also has remarkable activity as organocatalyst, and it is of structural importance for many folded polypeptides. Here we show that prolinyl nucleotides with a phosphoramidate linkage are active building blocks in enzyme- and ribozyme-free copying of RNA in the presence of monosubstituted imidazoles as organocatalysts. Both dinucleotides and mononucleotides are incorporated at the terminus of RNA primers in aqueous buffer, as instructed by the template sequence, in up to eight consecutive extension steps. Our results show that condensation products of amino acids and ribonucleotides can act like nucleoside triphosphates in media devoid of enzymes or ribozymes. They are metastable building blocks, readily activated by catalysts, helping to explain why the combination of α-amino acids and nucleic acids was selected in molecular evolution.