Aptamers from random sequence space: Accomplishments, gaps and future considerations

Aptamers are molecular recognition elements made of nucleic acids. Diverse synthetic aptamers have been discovered in a large number of SELEX experiments since 1990. This review begins with the analysis of these SELEX experiments by examining the range of targets as well as the affinity and specificity for these targets by DNA, RNA or modified nucleic acid aptamers generated from these experiments. This is followed by comparisons of synthetic aptamers with natural RNA aptamers from riboswitches and with some of the best naturally occurring protein based recognition elements for proteins and small molecules. These comparisons reveal the gaps between man-made aptamers and natural recognition elements. We then put forward a series of ideas for consideration by the aptamer community towards developing better aptamers to solve real world problems. These include performing aptamer selections with libraries containing larger random sequence domains to derive larger aptamers with more intricate structures, conducting more reselection experiments using mutagenized DNA libraries based on initially selected aptamer sequences to search for better members of an aptamer family, selecting aptamers that are programmed to recognize two or more different epitopes of the same target in order to build multivalent aptamers for increased affinity, expanding the effort of selecting aptamers using modified nucleic acids with enhanced chemical functionalities, innovating SELEX methods to drive for the selection of aptamers with truly outstanding affinity and specificity, and having terminal applications in mind when creating new aptamers so that they are highly functional in the environment where the applications are planned.