Session
Speaker
Discovery of Specific Inhibitors against Helicobacter
pylori by HTS of Large Chemical Libraries Using a Protein Stability
Assay
Javier Sancho
Spain
Infectious diseases can be fought with small molecules that
bind to the target (typically a protein) and block its activity. A
general consequence of ligand binding to proteins is an increase in
protein stability, which can be easily detected from thermal unfolding
curves. On the other hand, large chemical libraries with significant
diversity and good pharmacokinetic properties have become available
to groups in academia, thus allowing the developing of HTS programs
for drug discovery. We have discovered, using this approach, submicromolar
inhibitors of the essential flavodoxin from Helicobacter pylori.
Out of 10,000 molecules tested, 3 kill the bacteria while exhibiting
no apparent toxicity in mice after oral administration. Variants of
them are being synthesized and tested with the aim of developing new
and specific inhibitors against the infection by Helicobacter
pylori.1 Similar strategies
in our group have successfully discovered pharmacological chaperons2
and are now being used to identify inhibitors of the aggregation of
the amyloid beta peptide and of amyline.
1 N. Cremades, A. Velázquez-Campoy,
M. Martínez-Júlvez, J. L. Neira, I. Pérez-Dorado,
J. Hermoso, P. Jiménez, A. Lanas, P. S. Hoffman and J. Sancho.
Discovery of specific flavodoxin inhibitors as potential therapeutic
agents against Helicobacter pylori infection. ACS Chem. Biol.
(2009), In Press.
2 A.L Pey, M. Ying, N. Cremades,
A. Velazquez-Campoy, T. Scherer, B. Thöny, J. Sancho & A.
Martinez.
Identification of pharmacological chaperones as potential therapeutic
agents to treat phenylketonuria
J. Clin. Invest. (2008), 118: 2858-2867.
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