Research at the Department of
Bioorganic Chemistry
Summary of the current
research
activities
(Research
Projects) :
The current research activities at the Department are
conducted in the
following
frontiers:
- New
synthetic
methodologies for RNA, DNA, and their modified analogs as potential
DNA/RNA-directed
therapeutics
(siRNAs,
antisense,
triplexing
agent,
etc),
including synthetic and physico-chemical aspects
of monosaccharide, heterocyclic, and phospholipid, phosphorylating and
protecting group chemistry. Nucleos(t)ide chemistry to design specific
inhibitors against virus-specific enzymes and tumor cells are also
included.
Design and synthesis of new conformationally-constrained nucleic acids
and their enzymology to develop effective antisense oligos and siRNAs
to
enhance blood serum stability and facilitate delivery [J.
Am. Chem. Soc. 128,15173 (2006), J.
Org. Chem. 71, 299 (2006). J.
Am. Chem. Soc. 126, 11484 (2004); Nucleic
Acids Research 32, 5791 (2004).]
- Design
and development of nucleic acids drugs to cure Huntington desease
- Development
of
active
antibiotic compounds againts multiple drug resistant and
extensive drug resistant strains of tuberculosis and hospital pathogens.
- Stereospecific isotope labeling techniques to create the
Uppsala "NMR-windows" in order to simplify the NMR spectra to
elucidate
the structures of large biological functional DNA and RNA.
- Synthesis and structure of
lariat- and branched-RNA to understand the mechanism of splicing
and
the self-cleavage reaction of the RNA catalysis.
- Synthesis
and
enzymatic
properties
of the conformationally-constrained nucleosides
and nucleotides as potential therapeutics for the down-regulation
of
genes.
- Elucidation
of
Bioorganic
Mechanisms using synthetic physical and structural (NMR)
chemistry to model transition state or the intermediate of biochemical
reactions, such as splicing, RNA catalysis, and RNA-RNA-ligand or
RNA-DNA-ligand
interactions .
- The infrastructure
includes 500/600 MHz NMR, fully equipped organic chemistry lab and
computational
facilities to conduct interdisciplinary research at the interface of
chemistry
and biology of DNA/RNA.
- International networks/projects: The EU research project RIGHT
- "RNA Interference Technology as Human Therapeutic Tool", involving 22
EU research institutes as an "Integrated Project" with 13 million Euros
of funding by the EU FP6 program. http://www.ip-right.org/
- Multidisciplinary research (Chemistry/Structure/Enzymology)
at the
frontier
of the bioorganic chemistry of nucleic acid. Our consortium on the
chemical
biology of RNA (Uppsala RNA Research Center, URRC) is the only
recipient
of the Linneus
Grant
in
UU.
- Fundamental studies are being carried out to understand the
stereoelectronic
forces that are responsible (besides H-bonding, electrostatics,
hydrophobic
and stacking interactions) for the self-organisation of DNA and RNA by
a combination of NMR
spectroscopy and computational
methods. The concept of Stereoelectronic
effects in DNA and RNA and their structural and functional
implications.
- Research into single-strand DNA and RNA conformation which
showed that
purine-rich single-strand oligo-DNA and -RNA are well pre-organized to
helical form - not random coils as it was originally thought. The
structure
of the self-assembled single-strand oligo-DNA and -RNA is very much
reminiscent
of their double-stranded counterparts [Biochemistry
44,
5390
(2005);
ibid, 43 (51), 15996 (2004)].
- Have shown that all
internucleotidic
phosphodiester bond in RNA are not chemically equivalent, and their
reactivity depends upon the sequence-context governed by specific
intrinsic
electrostatic interactions [Org.
Biomol. Chem, 4, 928 - 941 (2006)].
- Development of new solid-phase oligo-RNA synthesis protocol
using new
2'-O-TEM
protecting group [Org.
Biomol. Chem. 5, 333 - 343 (2007)].
- Structure determination of nucleosides and oligonucleotides
and their
complexes
with various ligands by using high-field NMR
spectroscopy and computational
methods (molecular mechanics and dynamics as well as quantum
chemistry)
Goals
- The synthetic activities (Research
Projects) are expected to lead us to the development of new
chemicals
and reagents as potential gene-directed pharmaceuticals and diagnostics
for the down-regulation of gene expression.
- Elucidation of Bioorganic Mechanisms using synthetic
physical and
structural
(NMR) chemistry to model transition state or the intermediate of
biochemical
reactions, such as splicing, RNA catalysis, and DNA/RNA-ligand
interactions.
- The structural studies encompassing both high-field NMR and
computational
chemistry (Research
Projects) are being used to shed light on the general principles of
stereoelectronic make-up, electrostatics, hydrogen-bonding, hydration
and
hydrophobic interactions of nucleosides, nucleotides and
oligonucleotides
and their complexes.
- On the other hand, the kinetic analysis of important
chemical reactions
such as RNase H promoted cleavage of the hybrid duplex of the antisense
oligo and the target RNA sheds light on the energetics of the
intermediates
and their transition states to better understand the design principles
of the enzyme substrates.
- Thus a dynamic and iterative interplay of
Synthetic
Chemistry, Enzymolgy of Nucleic Acid-Protein Complexes and
Structuralstudies
using NMR and Computation is being found useful for the design and
synthesis of improved nucleic acid based therapeutics or inhibitors, as
well as to further our understanding of how the structure and dynamics
of nucleic acids and its complexes with various ligands dictate their
unique
biological function.
- We expect this Bioorganic Approach
will enhance our understanding at the Chemistry-Biology interface.
Are you interested in participating
in our
research?
We welcome new scientific collaborators both for doctoral and
postdoctoral studies. For some hints for new recruits for doctoral studies, see "How
to become a Ph.D student".
Contact Prof.
Jyoti Chattopadhyaya by e-mail, phone
or
mail for more details. |
