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A structural biology study of schistosomiasis
P a r t i c i p a n t s :
Adriana Erica Miele, professor; Francesco Angelucci, postdoc
fellow; Daniela Dimastrogiovanni, PhD student;
Giovanna Boumis, technician.
C o l l a b o r a t i o n s :
Istituto di Biologia Cellulare, CNR, Monterotondo, Roma (Prof.
Donato Cioli, Prof. Piero Liberti, Dr. Livia Pica Mattoccia).
Schistosomiasis is a widespread human parasitic disease
caused by helminth parasites of the genus
Schistosoma. The life cycle of the parasite depends
on an intermediate and a definitive host, a freshwater
mollusc and a mammal respectively. Because of
the requirements of the intermediate host, the infection
is restricted to tropical and subtropical climates
and to the proximity of freshwater sources; it has
nevertheless a major impact on human health and
development since it may frustrate the attempts to
develop agriculture. Efforts directed to the control
of the intermediate host and to develop a vaccine for
humans have been scarcely successful, and therefore
therapy of conclamate cases remains the strategy of
choice.
The therapy of schistosomiasis relies mainly on one
chemotherapeutic agent, praziquantel, although
several other compounds exert anti-parasitic
effects. Thus, development of drug resistance is an
impending danger, with serious implications for the
health protection of an estimated 200 millions people.
This rational and legitimate concern might
now begin to be relieved thanks to the increased
knowledge of the genome and the molecular biology
of the schistosome, which has lead to the recent
proposal of new classes of compounds that could
represent novel sources of drugs against schistosomiasis.
We focussed our studies on two main potential
drug targets (Cioli et al., Trends Parasitol. 2008,
24:379-82), namely the proteins thioredoxin glutathione
reductase (TGR) and cyclophylin (Cyp)
Pathogenetic mechanisms of microbially associated diseases - AREA 2
Principal investigator: Andrea Bellelli
Professor of Biochemistry
Dipartimento di Scienze Biochimiche “A. Rossi Fanelli”
Tel: (+39) 06 49910955; Fax: (+39) 06 4440062
Andrea.bellelli@uniroma1.it
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both from S. mansoni; other potential targets are
also being considered.
TGR is a key flavoenzyme expressed by schistosomes
that bridges the two detoxification pathways
of thioredoxin and of glutathione. The enzyme is
crucial for the parasite survival in the definitive
host's organism (Kuntz et al., PLoS Med. 2007, 4,
e206).We solved the crystal structure of TGR from
S. mansoni (SmTGR), deleted in the last two
residues at 2.2 Å resolution (Angelucci et al.,
Proteins 2008, 72:936-45). The structure reveals the
peculiar architecture of this chimeric enzyme: the
small Glutaredoxin (Grx) domain at the N-terminus
is joined to the large thioredoxin reductase
(TR) one via an extended complementary surface,
involving residues not conserved in the Grx superfamily;
the TR domain interacts with an identical
partner via its C-terminal domain, forming a dimer
with a twisted "W" shape. Although lacking the
penultimate Selenocysteine residue (Sec), the
enzyme is still able to reduce oxidized glutathione.
These data update the interpretation of the interdomain
communication in TGR enzymes. SmTGR
is the target of two classical antischistosomal
drugs, emetic tartrate and oltipraz, that are not any
more employed in therapy because of their severe
side effects. Moreover it has been demonstrated that
SmTGR is the target of auranofin, a gold compound
used for the treatment of rheumatoid arthritis
but capable of killing the schistosomes in vitro
and in vivo. Finally, some new compounds have
been discovered that inhibit SmTGR, e.g. the derivatives
of furoxane (Sayed et al., Nat Med. 2008,
14:407-12). Our structure may provide the information
necessary for improving any of these lead compounds,
yielding substantial improvements in specificity
and activity.
The immunosuppressant cyclosporin A has been
shown to significantly diminish worm burden in mice
infected with S. mansoni (Khattab et al., Exp Parasitol.
1998, 90:103). Given the well established interaction