High-throughput screening finds chloroquine effective against lethal
6 March 2009
Two highly lethal viruses that have emerged in recent outbreaks have
been found using high-throughput screening techniques to be susceptible
to chloroquine. Chloroquine is a long-established drug used to prevent
and treat malaria. The study was carried out by researchers in the US at
Weill Cornell Medical College, Cornell University's medical school.
Due to the study's significance, it was published this week online in
the Journal of Virology, in advance of the print issue, and
will be highlighted as an editor's 'spotlight' in the first May issue
The two henipaviruses that are the subject of the study — Hendra
Virus (HeV) and Nipah Virus (NiV) — emerged during the 1990s in
Australia and Southeast Asia. Harboured by fruit bats, they cause
potentially fatal encephalitis and respiratory disease in humans, with a
devastating 75% fatality rate. More recently, NiV outbreaks in
Bangladesh involving human-to-human transmission have focused attention
on NiV as a global health concern.
The researchers, based in Weill Cornell's pediatrics department, were
surprised by their discovery that chloroquine, a safe, low-cost agent
that has been used to combat malaria for more than 50 years, is a highly
active inhibitor of infection by Hendra and Nipah.
"The fact that chloroquine is safe and widely used in humans means
that it may bypass the usual barriers associated with drug development
and move quickly into clinical trials," says Dr Anne Moscona, professor
of pediatrics and microbiology & immunology at Weill Cornell Medical
College and senior author of the study. She is also vice chair for
research of pediatrics at NewYork-Presbyterian Hospital/Weill Cornell
"Chloroquine stands a good chance of making it through the
development process in time to prevent further outbreaks of these deadly
infections," adds Dr Moscona.
Like the avian flu, SARS, and Ebola viruses, Hendra and Nipah are
zoonotic pathogens. That means they originate in certain animals but can
jump between animal species and between animals and humans. There are
currently no vaccines or treatments against the two henipaviruses, which
are listed by the US government as possible bioterror agents.
Along with Dr Moscona and her team, the study's lead author and
fellow faculty member Dr Matteo Porotto, in collaboration with Dr Fraser
Glickman at Rockefeller University's High Throughput Screening Resource
Center, developed a screening test that substituted a non-lethal cow
virus for the real thing. They engineered a viral hybrid, called a
pseudotype, featuring proteins from the Hendra virus on its surface but
lacking Hendra's genome. The pseudotype behaves in every way like its
deadly counterpart, but ultimately, it only succeeds in replicating its
The researchers designed their screening technique specially to
reflect molecular reactions at several stages of the pathogen's
lifecycle. Instead of focusing exclusively on how the virus enters the
cell, like other pseudotyped screening assays, explains Dr Porotto, the
researchers were able to consider how Hendra matures, buds, and exits
the cell, and to screen for compounds that interfere with its
development at various stages.
Chloroquine does not prevent Hendra or Nipah virus from entering the
cell. Instead, the chloroquine molecule appears to block the action of a
key enzyme, called cathepsin L, which is essential to the virus's growth
and maturation. Without this enzyme, newly formed Hendra or Nipah
viruses cannot process the protein that permits the viruses to fuse with
the host cell. Newly formed viruses then cannot spread the infection; in
other words, they can invade, but cannot cause disease.
Several other zoonotic viruses depend on cathepsin L — most notably,
Ebola. "Our findings, and our methods, could easily be applied to the
study of Ebola and other emerging diseases," Dr Porotto says.
The researchers are confident that the use of this new screening
strategy will build up the number of viral targets available for study
and expand the antiviral research field at a time when new antivirals
are desperately needed for emerging pathogens. The group anticipates
collaborating on field studies in the near future, to assess the
potential for efficacy of chloroquine and related compounds in Nipah-infected
The researchers included Gianmarco Orefice, Christine Yokoyama and
Michael Sganga of Weill Cornell Medical College; Dr Bruce Mungall and
Mohamad Aljofan of CSIRO Livestock Industries, Geelong, Australia;
Ronald Realubit and Dr Fraser Glickman of Rockefeller University; and Dr
Michael Whitt of the University of Tennessee Health Science Center.
1. Matteo Porotto, Gianmarco Orefice, Christine Yokoyama, Bruce
Mungall, Ronald Realubit, Michael Sganga, Mohamad Aljofan, Michael
Whitt, Fraser Glickman, and Anne Moscona. Simulating henipavirus
multicycle replication in a screening assay leads to identification of a
promising candidate for therapy. Journal of
Virology. doi:10.1128/JVI.00164-09. published online ahead
of print on 4 March 2009.
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