Covalent aptamers: agents with promising therapeutic and diagnostic potential

Small molecule- and antibody-based approaches have shown tremendous success in both therapeutic and diagnostic applications. Aptamers, which are engineered nucleic acid ligands for proteins, have not found similar broad applicability, potentially due to their susceptibility to nuclease-mediated degradation and short engagement times of their targets. One approach to mitigate these issues is the use of covalent aptamers. Here, the aptamer sequence is functionalized with an electrophilic motif, combining the high specificity of aptamer-protein binding with the ability to form a permanent covalent bond at nucleophilic residues on the target protein. These electrophilic motifs can be either non-cleavable, allowing for the formation of aptamer-protein conjugates, or cleavable, allowing for transfer of a payload onto the target protein. The chemical structures of these motifs define their functions which range from protein detection to targeted protein degradation. The covalent bond formed between the electrophile and a nucleophilic amino acid sidechain at the protein surface dramatically increases the engagement time and duration of action of the functional moiety. In this review, we summarize efforts in establishing, understanding, and applying the chemistry of covalent aptamers.