JVI Accepts, published online ahead of print on 4 March 2009

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J. Virol. doi:10.1128/JVI.00164-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Simulating henipavirus multicycle replication in a screening assay leads to identification of a promising candidate for therapy

Matteo Porotto, Gianmarco Orefice, Christine Yokoyama, Bruce Mungall, Ronald Realubit, Michael Sganga, Mohamad Aljofan, Michael Whitt, Fraser Glickman, and Anne Moscona^*

Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021; Australian Animal Health Laboratory, CSIRO Livestock Industries, 5 Portarlington Road, Geelong, Australia 3220; Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163; High Throughput Screening Resource Center, The Rockefeller University, New York, NY 10065

^* To whom correspondence should be addressed. Email: anm2047{at}med.cornell.edu.

Nipah (NiV) and Hendra (HeV) viruses are emerging zoonotic paramyxoviruses that cause encephalitis in humans, with fatality rates of up to 75%. We designed a new high-throughput screening (HTS) assay for inhibitors of infection, based on envelope glycoprotein pseudotypes. The assay simulates multicycle replication and thus identifies inhibitors that target several stages of the viral life cycle, but still can be carried out under Biosafety Level-2 (BSL-2) conditions. These features permit a screen for antivirals for emerging viruses and select agents that would otherwise require BSL-4 HTS facilities. Screening of a small compound library identified several effective molecules, including the well-known compound chloroquine as a highly active inhibitor of pseudotyped virus infection. Chloroquine inhibited infection with live HeV and NiV at a concentration of 1µM in vitro (IC50=2µM), lower than the plasma concentrations present in humans receiving chloroquine treatment for malaria. The mechanism for chloroquine's antiviral action is likely to be inhibition of cathepsin L, a cellular enzyme that is essential for processing of the viral fusion glycoprotein and maturation of newly budding virions. Without this processing step, virions are not infectious. The identification of a compound that inhibits a known cellular target important for viral maturation, but that had not previously been shown to have antiviral activity for henipaviruses, highlights the validity of this new screening assay. Given the established safety profile and broad experience with chloroquine in humans, the results described here provide an option for treating individuals infected by these deadly viruses.

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