Interrogating Aptamer Chemical Space Through Modified Nucleotide Substitution Facilitated by Enzymatic DNA Synthesis

Chemical modification of aptamers is an important step to improve their performance and stability in biological media. This can be performed either during their identification (mod‐SELEX) or after the in vitro selection process (post‐SELEX). In order to reduce the complexity and workload of the post...

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Published in:Chembiochem : a European journal of chemical biology 2024-01, Vol.25 (1), p.e202300539-n/a
Main Authors: Niogret, Germain, Bouvier‐Müller, Alix, Figazzolo, Chiara, Joyce, Jack M., Bonhomme, Frédéric, England, Patrick, Mayboroda, Olena, Pellarin, Riccardo, Gasser, Gilles, Tucker, James H. R., Tanner, Julian A., Savage, G. Paul, Hollenstein, Marcel
Format: Article
Language:English
Subjects:
Aptamers
Aptamers, Nucleotide - chemistry
bioisosteres
Chemical modification
Chemical Sciences
Chemical synthesis
Cubane
cubanes
DNA
DNA biosynthesis
Enzymatic synthesis
Medicinal Chemistry
Nucleic Acids
Nucleotides
polymerases
post-SELEX
SELEX Aptamer Technique - methods
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Summary:Chemical modification of aptamers is an important step to improve their performance and stability in biological media. This can be performed either during their identification (mod‐SELEX) or after the in vitro selection process (post‐SELEX). In order to reduce the complexity and workload of the post‐SELEX modification of aptamers, we have evaluated the possibility of improving a previously reported, chemically modified aptamer by combining enzymatic synthesis and nucleotides bearing bioisosteres of the parent cubane side‐chains or substituted cubane moieties. This method lowers the synthetic burden often associated with post‐SELEX approaches and allowed to identify one additional sequence that maintains binding to the PvLDH target protein, albeit with reduced specificity. In addition, while bioisosteres often improve the potency of small molecule drugs, this does not extend to chemically modified aptamers. Overall, this versatile method can be applied for the post‐SELEX modification of other aptamers and functional nucleic acids. Post‐SELEX modification of aptamers allows to improve their performance but comes at the cost of uncertain and labor‐intensive structure activity relationship studies. Here, we have evaluated the possibility of improving a previously reported, chemically modified aptamer by combining enzymatic synthesis and nucleotides bearing bioisosteres of the parent cubane side‐chains or substituted cubane moieties. This method lowers the synthetic burden associated with post‐SELEX approaches and allowed to identify one additional sequence that maintains binding to the PvLDH target protein, albeit with reduced specificity.
ISSN:1439-4227
1439-7633
DOI:10.1002/cbic.202300539