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Structural Biology 2018
Volume: 4
Biochemistry & Molecular Biology Journal
Page 71
March 15-16 2018
Barcelona, Spain
10
th
Edition of International Conference on
Structural Biology
T
rypanosomatid infections are the cause of African sleeping
sickness, leishmaniasis, and Chagas disease. The parasites
use glycosomes, organelles similar to peroxisomes to
compartmentalize glucose metabolism. The malfunction of this
compartmentalization releases glucose processing enzymes
to the cytoplasm causing runaway glucose phosphorylation,
ATP depletion and subsequent cell death. The proteins Pex14
and Pex5 are essential components of the glycosomal import
machinery. They bind each other by a direct protein-protein
interface. It has been shown that in the absence of Pex14 glucose
is toxic to the parasite. We have determined the structure of the
Pex14-Pex5 complex to develop a line of small molecule inhibitors
able to disrupt the Pex14-Pex5 interaction in a competitive way.
The compounds identified proved active against
Trypanosoma
brucei in vivo
and in cell-based assays. We have confirmed their
disruptive function on parasites glycosomes. Simultaneously,
the compounds appear to be of limited toxicity to the human cell
lines. Our results confirm that targeting the Pex14-Pex5 interface
is a viable therapeutic strategy to treat both human and animal
trypanosomiases.
grzegorz.popowicz@helmholtz-muenchen.deTrypanosomatids parasites Achille’s heel: targeting glycosome
biogenesis
Grzegorz M Popowicz, Maciek Dawidowski, Leonidas Emmanouilidis, Vishal
Kalel, Wolfgang Schliebs, Ralf Erdmann
and
Michael Sattler
Helmholtz Zentrum München, Germany
Biochem Mol biol J, Volume 4
DOI: 10.21767/2471-8084-C1-009