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

Matteo Porotto, Gianmarco Orefice, Christine C. Yokoyama, Bruce A. Mungall, Ronald Realubit, Michael L. Sganga, Mohamad Aljofan, Michael Whitt, Fraser Glickman, Anne Moscona

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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 it 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 otherwise would require BSL-4 HTS facilities. The screening of a small compound library identified several effective molecules, including the well-known compound chloroquine, as highly active inhibitors of pseudotyped virus infection. Chloroquine inhibited infection with live HeV and NiV at a concentration of 1 μM in vitro (50% inhibitory concentration, 2 μM), which is less than the plasma concentrations present in humans receiving chloroquine treatment for malaria. The mechanism for chloroquine's antiviral action likely is the inhibition of cathepsin L, a cellular enzyme that is essential for the processing of the viral fusion glycoprotein and the maturation of newly budding virions. Without this processing step, virions are not infectious. The identification of a compound that inhibits a known cellular target that is 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.

Original languageEnglish (US)
Pages (from-to)5148-5155
Number of pages8
JournalJournal of Virology
Volume83
Issue number10
DOIs
StatePublished - May 1 2009

Fingerprint

Henipavirus
chloroquine
Chloroquine
screening
therapeutics
Antiviral Agents
assays
virion
Virion
viruses
Hendra Virus
viral fusion proteins
Hendra virus
Viral Fusion Proteins
infection
High-Throughput Screening Assays
Viruses
cathepsin L
Cathepsin L
Respirovirus

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Porotto, M., Orefice, G., Yokoyama, C. C., Mungall, B. A., Realubit, R., Sganga, M. L., ... Moscona, A. (2009). Simulating henipavirus multicycle replication in a screening assay leads to identification of a promising candidate for therapy. Journal of Virology, 83(10), 5148-5155. https://doi.org/10.1128/JVI.00164-09

Simulating henipavirus multicycle replication in a screening assay leads to identification of a promising candidate for therapy. / Porotto, Matteo; Orefice, Gianmarco; Yokoyama, Christine C.; Mungall, Bruce A.; Realubit, Ronald; Sganga, Michael L.; Aljofan, Mohamad; Whitt, Michael; Glickman, Fraser; Moscona, Anne.

In: Journal of Virology, Vol. 83, No. 10, 01.05.2009, p. 5148-5155.

Research output: Contribution to journalArticle

Porotto, M, Orefice, G, Yokoyama, CC, Mungall, BA, Realubit, R, Sganga, ML, Aljofan, M, Whitt, M, Glickman, F & Moscona, A 2009, 'Simulating henipavirus multicycle replication in a screening assay leads to identification of a promising candidate for therapy', Journal of Virology, vol. 83, no. 10, pp. 5148-5155. https://doi.org/10.1128/JVI.00164-09
Porotto, Matteo ; Orefice, Gianmarco ; Yokoyama, Christine C. ; Mungall, Bruce A. ; Realubit, Ronald ; Sganga, Michael L. ; Aljofan, Mohamad ; Whitt, Michael ; Glickman, Fraser ; Moscona, Anne. / Simulating henipavirus multicycle replication in a screening assay leads to identification of a promising candidate for therapy. In: Journal of Virology. 2009 ; Vol. 83, No. 10. pp. 5148-5155.
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