Nucleobase Amino Acids in the Development of Amide-Linked Oligonucleotide Mimics

Although peptide nucleic acids (PNAs) have been extensively used in antisense strategies, the lack of any side chain in the PNA backbone deprives them of having any protein-like tertiary structures, limiting their use in nucleic acid-protein interactions. To overcome this limitation, scientists have developed hybrid monomeric structures like nucleobase amino acids (NBAs) where canonical nucleobases are covalently attached to natural or unnatural amino acid side chains, making them amenable to incorporation into peptides, proteins, and PNAs using solid- or solution-phase peptide synthesis. The resulting assemblies are capable of recognizing their complementary oligonucleotides as well as having the ability to form well-defined secondary/tertiary protein-like structures for enhanced nucleic acid-protein interactions. This perspective article chronicles the developments in this area of research over the years.