Aptamers are oligonucleotides that fold into intricate three-dimensional conformations with high affinity for a specific molecular target. This ability can be harnessed to design biosensors, which function by inducing fluorescence enhancement of fluorogenic ligands under molecular confinement when the target is present. However, current aptamer designs have limitations in terms of accessibility, target configurability, and biological performance. To address these limitations, we are using synthetic organic chemistry approaches geared toward maximizing the potential of aptamers in both basic and translational research. Recently, we developed a powerful methodology to develop split aptamer designs for the detection of microRNAs. This methodology uses a fluorescent light-up mechanism with DNA sequences, which can be configured to detect diverse microRNAs in complex environments native to cells and tissues. To improve their performance in biological settings, we are synthetically developing a new generation of ligands that can undergo a bathochromic shift in the absorption and emission maxima upon binding the aptamer. The spectral shift can increase the photon penetration, minimize the photo-damage to biological samples, and decrease the background fluorescence. Another exciting research focus is to repurpose known aptamer sequences to sense environmental cues in the context of synthetic biology. These aptamers can be generated in cells through the transcription machinery, and the aptamer-containing cells can serve as biosensors for physiochemical changes in their surroundings. Using reactivity-guided pre-ligand designs, we successfully transformed Escherichia coli into live biosensors that detect redox alterations. These approaches, which leverage synthetic organic chemistry, are expected to expand the landscape of aptamer-based technologies with capabilities that go beyond their original, limited function.

Expanding the biological potential of nucleic acid aptamers by leveraging synthetic organic chemistry

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