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Research Projects at the Department of Bioorganic ChemistryIn the Department of Bioorganic Chemistry, the research involves the following projects (see List of Publications, links to PDF files of papers and its Guide as well as the List of Ph.D. Thesis from the Department.):
(A) Tethering of Various Chromophores/ hydrophobic moieties at 3' and or 5' end of AONs for delivery.
(B) Design and Synthesis of Various Conformationally-locked Nucleic Acids for conformational control in the pre-organization of Nucleic acids.
(C) Conformational analysis of antisense oligonucleotide/RNA duplexes as substrates for RNase H
(D) Small interfering RNAs (siRNAs)
(E) RNA interference in the context of human papillomavirus-related diseases
(F) EU research project on RNA Interference Technology as Human Therapeutic Tool (RIGHT)
2. Stereoelectronic Effects in
Nucleosides, Nucleotides and Nucleic Acids.
Uppsala "NMR Window" concept
pKa and hydration of 2'-OH in
RNA and its components
Lariat RNA (and consequently branched RNA) are intermediates in both nuclear pre-mRNA- and in the Group II self-splicing reaction. In the splicing reaction introns splice out by way of two successive transesterification reactions to give a processed mRNA. The cleavage at the 5'-junction in splicing is due to an intramolecular nucleophilic attack by a 2'-OH from within the intron. This creates a lariat-RNA intermediate with the 5'-end of the intron attached through a 2'->5'-phosphodiester bond to a residue near the 3'-end of the intron in the penultimate step of the splicing reaction. Subsequent cleavage at the 3'-junction results in the ligation of the exons and liberates the "free" intron in the form of a lariat. So, why is such lariat-RNA formed during the processing of pre-mRNA to functional RNA?(A) Introduction to Splicing and Lariat RNAs
(B) Summary of our Results
(C) Design of Ribozyme mimics
in the Self-assembly of DNA and RNA
We have however recently given concrete experimental evidences through pKa measurements (PDF 338, PDF 339, PDF 341, PDF 343, PDF 355, PDF 361) that the electrostatic interactions through the nearest-neighbors play an important role in steering both intra and intermolecular forces culminating into the self-assembly of both single-stranded and homo and hetero duplexes of DNA and RNA. We indeed could show that because of cross-modulation of the aromatic character (evidenced by a change of pKa ) amongst the nearest-neighbors as a result of electrostatic cross-talk, a clear pKa modulation take place. The generality of this pKa modulation by electrostatic cross-talk was also clearly shown in a much simpler coupled system consisting of pyridine-benzene, covalently linked by linker, which was transformed to pyridinium-benzene by simple change of the pH. The change of the aromatic character from pyridine to pyridinium was electrostatically registered by the phenyl group in the steric proximity by showing the pKa modulation [PDF 343].
Basis of the above pKa
modulation: Such electrostatic interactions are
also expected to steer recognition and interactions of
the ligand by the nucleic acid by the complementary
electric field. The overall stability of nucleic
acids, as well as their complexes with a ligand, is
considered a sum of contributions of intermolecular
electrostatic interactions, hydrogen bonding, van der
Waals and hydrophobic interactions. ( PDF
of the pseudoaromatic character in single-stranded
RNA by nearest-neighbor interactions
Phase Synthesis of RNA
of Nucleotide-Peptide Conjugates
16. Projects to
combat infectious diseases