RNA damage; chemically modified oligonucleotides; RNA therapeutics; antisense agents
Frei Sibylle, Katolik Adam K, Leumann Christian J (2019), Synthesis, biophysical properties, and RNase H activity of 6’-difluoro[4.3.0]bicyclo-DNA, in Beilstein Journal of Organic Chemistry
, 15, 79-88.
Frei Sibylle, Istrate Andrei, Leumann Christian J (2018), 6’-Fluoro[4.3.0]bicyclo nucleic acid: synthesis, biophysical properties and molecular dynamics simulations, in Beilstein Journal of Organic Chemistry
, 14, 3088-3097.
Willi Jessica, Küpfer Pascal, Evéquoz Damien, Fernandez Guillermo, Katz Assaf, Leumann Christian, Polacek Norbert (2018), Oxidative stress damages rRNA inside the ribosome and differentially affects the catalytic center, in Nucleic Acids Research
, 46(4), 1945-1957.
Istrate Alena, Katolik Adam, Istrate Andrei, Leumann Christian J. (2017), 2′β-Fluoro-Tricyclo Nucleic Acids (2′F-tc-ANA): Thermal Duplex Stability, Structural Studies, and RNase H Activation, in Chemistry - A European Journal
, 23(43), 10310-10318.
Diafa Stella, Evéquoz Damien, Leumann Christian J., Hollenstein Marcel (2017), Enzymatic Synthesis of 7′,5′-Bicyclo-DNA Oligonucleotides, in Chemistry - An Asian Journal
, 12(12), 1347-1352.
Evéquoz Damien, Leumann Christian J. (2017), Probing the Backbone Topology of DNA: Synthesis and Properties of 7′,5′-Bicyclo-DNA, in Chemistry - A European Journal
, 23(33), 7953-7968.
Roethlisberger Pascal, Kaliginediand Veerabhadrarao, Leumann Christian J. (2017), Modulation of Excess Electron Transfer through LUMO Gradients in DNA Containing Phenanthrenyl Base Surrogates, in Chemistry - A European Journal
, 23(9), 2022-2025.
Schuermann David, Scheidegger Simon P., Weber Alain R., Bjørås Magnar, Leumann Christian J., Schär Primo (2016), 3CAPS – a structural AP–site analogue as a tool to investigate DNA base excision repair, in Nucleic Acids Research
, 44(5), 2187-2198.
Roethlisberger P., Istrate A., Marcaida Lopez M. J., Visini R., Stocker A., Reymond J.-L., Leumann C. J. (2016), X-ray structure of a lectin-bound DNA duplex containing an unnatural phenanthrenyl pair, in Chemical Communications
, 52(26), 4749-4752.
In this grant application we present three projects that are situated in the area of oligonucleotide chemistry and biology and that address questions of current interest in the fields of oligonucleotide therapy, artificial genetic systems and RNA damage and its biological consequences.In the first project which is grouped into sub-projects A-D we will focus mostly on understanding and improving the molecular properties of tricyclo-DNA (tc-DNA) which has been developed in our laboratory and is currently in consideration for clinical trials. The goal of sub-project A is to obtain high resolution NMR structures on tc-DNA/RNA duplexes and on other modified tc-DNA duplexes. This is necessary because we have been unsuccessful in the past to obtain high resolution structures of tc-DNA by X-ray crystallography. Knowing the structure in detail, however, is an important prerequisite to determine potential sites for further chemical modification. In sub-project B we will focus on tc-DNA modifications carrying fluorine substituents in various positions. This work is inspired by recent reports in which differential protein binding of fluorinated nucleic acids is described. Furthermore, due to conformational control of the ribose unit in tc-DNA, we expect to overcome current limitations in the use of tc-DNA/DNA mixmers, and may be able to generate a tc-DNA version that is able to elicit RNase H activity. In sub-project C we propose novel tc-DNA modifications that vary in their degree of hydrophobicity. With this we aim at improving cellular uptake and, eventually, at generating therapeutically active oligonucleotides that need no phosphorothioate backbone. Sub-project D is overarching all activities in this project by collecting all modifications and determine their plasma protein binding pereferences as well as their propensity to form nanoparticles. This will shed light on the importance of nanoparticle formation with respect to cellular uptake which is of great current interest.In the second project we want to develop an artificial genetic system based on 7’-5’-bc-DNA. This modification has previously been investigated in our group and shows the required chemical properties. Preliminary experiments show that this modification is successfully processed by DNA polymerases. We therefore propose to perform molecular evolution by SELEX with this modification. We expect the emergence of different folding patters for single strands which may be beneficial for the binding properties of corresponding aptamers and DNAzymes.The third project deals with questions on the biological consequences of oxidative RNA base damage. In two sub-projects we will determine the mechanism of base decay of 5-hydroxy-pyrimidines that are the primary products of oxidation by reactive oxygen species and will investigate the consequences of site-specific oxidative base lesions in the ribosome on translation (in collaboration with Prof. N. Polacek in or department).