Aptamers are single-stranded DNA or RNA-based sequences that fold up to adopt a unique three-dimensional structure, allowing them to bind a specific target molecule.

Binding displays high specificity, and aptamers capable of distinguishing between closely related isoforms or different conformational states of the same protein have been generated. Binding affinity is also high. It is in the low nanomolar to picomolar range, which is comparable to the binding affinity of an antibody for the antigen against which it was raised.

Aptamer technology was first developed in 1990. It entails the initial generation of a large aptamer library, with subsequent identification of individual aptamers binding a target ligand via an appropriate selection strategy. DNA aptamer libraries are usually generated via direct chemical synthesis and amplified by PCR (Chapter 3). RNA libraries are usually generated by in vitro transcription of synthetic DNA libraries. Identification of specific aptamers binding the target molecule is most easily undertaken by an automated in vitro selection approach known as systematic evolution of ligands by exponential enrichment (SELEX). Most libraries contain up to 1015 species.

Because of their high binding specificity and affinity, aptamers (like antibodies) are/may prove useful for affinity-based purification, target validation and drug discovery, diagnostics and therapeutics. One such product (Macugen, Box 14.4) has been approved for general medical use to date. A modest number of additional aptamers are in clinical trials, aimed at treating conditions including infectious diseases, cancer and haemophilia.

Aptamers appear to display low immunogenicity; but, when administered systemically, they are quickly excreted via size-mediated renal clearance. In order to prevent renal removal, such aptamers are usually conjugated to PEG. PEG may also help further protect the aptamers from degradation by serum nucleases; native aptamers are prone to nuclease attack, but their half-lives can most effectively be extended via chemical modification, as discussed earlier in the context of antisense agents.

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