2′β-Fluoro-Tricyclo Nucleic Acids (2′F-tc-ANA): Thermal Duplex Stability, Structural Studies, and RNase H Activation

Istrate, Alena; Katolik, Adam; Istrate, Andrei; Leumann, Christian (2017). 2′β-Fluoro-Tricyclo Nucleic Acids (2′F-tc-ANA): Thermal Duplex Stability, Structural Studies, and RNase H Activation. Chemistry: a European journal, 23(43), pp. 10310-10318. Wiley 10.1002/chem.201701476

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We describe the synthesis, thermal stability, structural and RNase H activation properties of 2′β-fluoro-tricyclo nucleic acids (2′F-tc-ANA). Three 2′F-tc-ANA nucleosides (T, 5MeC and A) were synthesized starting from a previously described fluorinated tricyclo sugar intermediate. NMR analysis and quantum mechanical calculations indicate that 2′F-tc-ANA nucleosides prefer sugar conformations in the East and South regions of the pseudorotational cycle. UV-melting experiments revealed that non-consecutive insertions of 2′F-tc-ANA units in DNA reduce the affinity to DNA and RNA complements. However, an oligonucleotide with five contiguous 2′F-tc-ANA-T insertions exhibits increased affinity to complementary RNA. Moreover, a fully modified 10-mer 2′F-tc-ANA oligonucleotide paired to both DNA (+1.6 °C/mod) and RNA (+2.5 °C/mod) with significantly higher affinity compared to corresponding unmodified DNA, and similar affinity compared to corresponding tc-DNA. In addition, CD spectroscopy and molecular dynamics simulations indicate that the conformation of the 2′F-tc-ANA/RNA duplex is similar to that of a DNA/RNA duplex. Moreover, in some sequence contexts, 2′F-tc-ANA promotes RNase H-mediated cleavage of a complementary RNA strand. Taken together, 2′F-tc-ANA represents a nucleic acid analogue that offers the advantage of high RNA affinity while maintaining the ability to activate RNase H, and can be considered a prospective candidate for gene silencing applications.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

Istrate, Alena; Katolik, Adam; Istrate, Andrei and Leumann, Christian

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

1521-3765

Publisher:

Wiley

Language:

English

Submitter:

Christian Leumann

Date Deposited:

16 Oct 2017 14:47

Last Modified:

02 Aug 2018 02:30

Publisher DOI:

10.1002/chem.201701476

PubMed ID:

28477335

Uncontrolled Keywords:

antisense oligonucleotides nucleic acids thermal duplex stability tricyclo-DNA

BORIS DOI:

10.7892/boris.102424

URI:

https://boris.unibe.ch/id/eprint/102424

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