A functional group-guided approach to aptamers for small molecules

Aptameric receptors are important biosensor components, yet our ability to identify them depends on the target structures. We analyzed the contributions of individual functional groups on small molecules to binding within 27 target-aptamer pairs, identifying potential hindrances to receptor isolatio...

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Published inScience (American Association for the Advancement of Science) Vol. 380; no. 6648; pp. 942 - 948
Main Authors Yang, Kyungae, Mitchell, Noelle M, Banerjee, Saswata, Cheng, Zhenzhuang, Taylor, Steven, Kostic, Aleksandra M, Wong, Isabel, Sajjath, Sairaj, Zhang, Yameng, Stevens, Jacob, Mohan, Sumit, Landry, Donald W, Worgall, Tilla S, Andrews, Anne M, Stojanovic, Milan N
Format Journal Article
LanguageEnglish
Published United States The American Association for the Advancement of Science 02.06.2023
Subjects
Amino acids
Aptamers
Functional groups
Fungicides
Leucine
Nucleotide sequence
Nucleotides
Oligonucleotides
Optimization
Ribonucleic acid
RNA
Voriconazole
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Summary:Aptameric receptors are important biosensor components, yet our ability to identify them depends on the target structures. We analyzed the contributions of individual functional groups on small molecules to binding within 27 target-aptamer pairs, identifying potential hindrances to receptor isolation-for example, negative cooperativity between sterically hindered functional groups. To increase the probability of aptamer isolation for important targets, such as leucine and voriconazole, for which multiple previous selection attempts failed, we designed tailored strategies focused on overcoming individual structural barriers to successful selections. This approach enables us to move beyond standardized protocols into functional group-guided searches, relying on sequences common to receptors for targets and their analogs to serve as anchors in regions of vast oligonucleotide spaces wherein useful reagents are likely to be found.
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Current affiliation: Rutgers New Jersey Medical School, Newark, NJ, USA.
Current affiliation: Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
Current affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
Author contributions: K.Y. and M.N.S. conceptualized the approach and designed the experiments; K.Y. isolated all aptamers for amines and amino acids, S.B. isolated aptamers for two amides, under her supervision. Z.C. synthesized voriconazole analogs. A.K. was a high-school student supported by the NSF and I.W. was an undergraduate student on an NSF REU (CCF1518715, 1763632). They both optimized and characterized aptamers. S.S. worked on epinephrine aptamers and Y.Z. was an undergraduate student who worked on isolating methylene blue aptamers, while supervised by S.T and K.Y. D.W.L. initiated research on aptamers in general, helped formulate an early version of this manuscript and suggested experiments, while J.S. and S.M. initiated the research on voriconazole aptamers and helped design parameters of initial selection experiments. T.S.W. initiated research on amino acids and ammonia and helped design early selection experiments with these targets. N.M.M. and A.M.A. produced and analyzed isothermal calorimetry data, while A.M.A also helped define neurotransmitter targets and parameters for selections. M.N.S. is responsible for all free energy calculations, he initially drafted the manuscript, while M.N.S., K.Y., N.M.M., and A.M.A. produced the final manuscript form, with input and approval from all authors.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.abn9859