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A synthetic genetic polymer with an uncharged backbone chemistry based on alkyl phosphonate nucleic acids
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Abstract
The physicochemical properties of nucleic acids are dominated by their highly charged
phosphodiester backbone chemistry. The polyelectrolyte structure decouples information
content (base sequence) from bulk properties such as solubility and has been proposed as a
defining trait of all informational polymers. However, this conjecture has not been tested
experimentally. Here, we describe the encoded synthesis of a genetic polymer with an
uncharged backbone chemistry: alkyl-phosphonate nucleic acids (phNA), in which the
canonical, negatively charged phosphodiester is replaced by an uncharged P-alkylphosphonodiester
backbone. Using synthetic chemistry and polymerase engineering, we
describe the enzymatic, DNA-templated synthesis of P-methyl- and P-ethyl-phNAs, and the
directed evolution of specific streptavidin-binding phNA aptamer ligands directly from
random-sequence, mixed P-methyl- / P-ethyl-phNA repertoires. Our results establish a first
example of the DNA-templated enzymatic synthesis and evolution of an uncharged genetic
polymer and provide a foundational methodology for their exploration as a source of novel,
functional molecules.
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ARANGUNDY-FRANKLIN, Sebastian, et al. A synthetic genetic polymer with an uncharged backbone chemistry based on alkyl phosphonate nucleic acids. Nature Chemistry. 2019. Vol. 11, num. 533–542. [consulted: 17 of June of 2026]. Available at: https://hdl.handle.net/2445/132998