Evolution of abiotic cubane chemistries in a nucleic acid aptamer allows selective recognition of a malaria biomarker

Significance We report the identification of a cubane-modified aptamer (cubamer) against the malaria biomarkerPlasmodium vivax lactate dehydrogenase (PvLDH). The cubamer contains the benzene isostere cubane, which is entirely alien to biology. The crystal structure of the cubamer–protein complex reveals a binding mechanism involving the formation of an unprecedented cubane pocket and an unusual C–H⋅⋅⋅O hydrogen bond. Importantly, the cubamer is capable of distinguishing the PvLDH from thePlasmodium falciparum LDH despite a very high sequence homology, which is impossible for unmodified aptamers. Finally, we have used the cubamer to detect PvLDH in a mimetic clinical situation. This approach blending medicinal chemistry and Darwinian evolution can easily be extended to other nonnatural, exotic functional groups.