Biocompatible and chemically synthesised long DNA and RNA

DNA structure is closely linked to its function as an information carrier. The orientation and spacing of nucleobases, as dictated by the phosphodiester backbone, ensures that DNA can be rapidly read by DNA polymerases. New areas of science have emerged where editing the structure and information content of DNA has become crucial and scientists have begun to look to the phosphodiester backbone as a potential customisation target. Modifying the backbone, whilst maintaining the correct enzymatic interactions has so far proven difficult.

Oxford researchers have developed a DNA backbone modification, which is simple to synthesise and, due to its similar size and shape to the classical phosphodiester backbone, behaves comparably in the presence of DNA polymerases. The technology allows for the accurate, site-specific modification of long strands of DNA, without dramatically affecting its function.

Next generation nucleic acids

Over evolutionary time, the molecular structure of DNA has become intricately linked with the enzymatic tools that propagate it. However, the rapidly growing fields of gene synthesis, genome editing, nanotechnology and epigenetics demand site-specific modifications of DNA and RNA structures, without compromising the enzymatic compatibility. Chemically modifying the backbone structures provides a promising new toolkit for introducing site-specific modifications to RNA and DNA via chemical ligation.

The backbone of the invention

In order to achieve truly biocompatible modified nucleic acids and analogues, it is necessary to closely mimic the phosphodiester backbone in order to maintain this readthrough capability.

High-fidelity readthrough of chemically ligated DNA

Researchers at the University of Oxford have developed a nucleic acid ligation technique for joining together synthetic DNA and RNA strands that is based around an amide functional group. It employs the same 5-bond spacing seen in natural phosphodiester linkages. The amide linkage can be formed with high efficiency and allows fast, high fidelity read-through by various polymerases.

This linkage could, therefore, be applied in gene synthesis and large-scale production of long modified nucleic acid constructs.

The main advantages of this method are:

  • Efficient synthesis and incorporation into DNA or RNA structures
  • Rapid and high-fidelity readthrough by DNA and RNA polymerases
  • The possibility of large-scale synthesis of long DNA and RNA constructs
  • Close structural mimic to naturally occurring phosphodiester

Patent protection

The Oxford technology is protected by a patent application with the potential for worldwide coverage. Oxford University Innovation is keen to talk to anyone interested in partnering with the aim of commercialising this technology.

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