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Recognition and sensing of low-epitope targets via ternary complexes with oligonucleotides and synthetic receptors


Oligonucleotide-based receptors or aptamers can interact with small molecules, but the ability to achieve high-affinity and specificity of these interactions depends strongly on functional groups or epitopes displayed by the binding targets. Some classes of targets are particularly challenging: for example, monosaccharides have scarce functionalities and no aptamers have been reported to recognize, let alone distinguish from each other, glucose and other hexoses. Here we report aptamers that differentiate low-epitope targets such as glucose, fructose or galactose by forming ternary complexes with high-epitope organic receptors for monosaccharides. In a follow-up example, we expand this method to isolate high-affinity oligonucleotides against aromatic amino acids complexed in situ with a nonspecific organometallic receptor. The method is general and enables broad clinical use of aptamers for the detection of small molecules in mix-and-measure assays, as demonstrated by monitoring postprandial waves of phenylalanine in human subjects.

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Figure 1: Basic principles of glucose recognition with boronic acid receptors and of the isolation of aptamers against complexes with receptors.
Figure 2: Results of three selection procedures against monosaccharides.
Figure 3: Results of three selection procedures against amino acids.
Figure 4: Measurement in human serum and real-time monitoring of postprandial waves.


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We are grateful to the National Science Foundation (CBET-1033288 and CBET-1026592), National Institutes of Health (RGM104960) and the Juvenile Diabetes Research Foundation (Innovative Program) for funding this research. We thank J. Loeb for help in correcting initial drafts of our manuscript.

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Authors and Affiliations



M.N.S. proposed and led the project. K-A.Y. isolated the aptamers listed in this report. S.P. and S.T. performed the synthetic and characterization work on the organic receptors. T.S.W. provided the clinical context and organized self-experiments, with B.K. providing technical support in these. M.B., M.H., P.P. and D.M.K. performed earlier experiments on glucose aptamers that eventually led to the development of the method described here. All co-authors participated in the design of their own experiments and analysis of data. M.N.S., T.S.W., K-A.Y. and S.T. wrote the manuscript, with the exception of synthetic procedures written by S.P.

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Correspondence to Tilla S. Worgall or Milan N. Stojanovic.

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Yang, KA., Barbu, M., Halim, M. et al. Recognition and sensing of low-epitope targets via ternary complexes with oligonucleotides and synthetic receptors. Nature Chem 6, 1003–1008 (2014).

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