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AN2690 ANTI FUNGAL COMPOUND |
New drug to attack tough fungus
New anti fungal drug compound
AN2690 kills fungal pathogens by
blocking enzyme.
June 26, 2007
Researchers have unveiled a new
mechanism to attack tough fungi which
cause infections in humans.
The Calfornia-based biotech company
Anacor Pharmaceuticals Inc., and the
European Molecular Biology Laboratory
(EMBL) outstation in Grenoble, France
have spotted a new compound that kills
fungal pathogens by blocking an enzyme
crucial for their protein synthesis,
according to Nature.
The compound, called AN2690, kills
fungi by blocking their ability to
make proteins.
AN2690 interferes with an enzyme
called leucyl-tRNA synthetase, which
is involved in translation, one of the
last steps in the process of turning a
gene's DNA code into a protein. The
process begins when the cell makes an
RNA version of the gene's code, called
messenger RNA. Ribosomes, the cell's
protein synthesis machinery, then
translate the messenger RNA into
protein by stitching together the
amino acids in the order specified by
the message. This requires the help of
molecules called tRNAs, which link the
code of the messenger RNA to the
correct amino acid.
Leucyl-tRNA synthetase is one of a
group of enzymes called aminoacyl-tRNA
synthetases that attach the correct
amino acid to each tRNA. Some of these
enzymes have two main functional
parts, or active sites: a site that
links the amino acid to the tRNA, and
a separate editing site that
proofreads this process and removes
wrongly added amino acids.
To find out how exactly AN2690 blocks
leucyl-tRNA synthetase Stephen Cusack,
Head of EMBL Grenoble, and his team
generated crystals of the enzyme bound
to tRNA in the presence of AN2690.
Examining them with the high-intensity
X-ray source at the European
Synchrotron Radiation Facility, Cusack
and his colleagues found that AN2690
sticks in the editing site of the
enzyme where it makes a very strong
bond to the end of the tRNA, trapping
it on the enzyme.
This stops the enzyme working and thus
blocks protein synthesis, killing the
fungal cell. The mechanism crucially
depends on a boron atom that is part
of AN2690, which is needed to link the
compound to the tRNA. It is the first
time that scientists describe such a
mechanism, suggesting boron containing
compounds as a promising new class of
drug candidates.
They believe that the same approach
could be adapted to target other
aminoacyl-tRNA synthetases with
editing sites and also other
pathogenic microbes. Now the
researchers are working towards
finding related antibacterial
compounds that could help counter the
problem of antibiotic resistance, the
report said
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