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J. Biol. Chem., Vol. 283, Issue 32, 21899-21908, August 8, 2008

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Inhibition of Chikungunya Virus Infection in Cultured Human Muscle Cells by Furin Inhibitors

IMPAIRMENT OF THE MATURATION OF THE E2 SURFACE GLYCOPROTEIN^*

Simona Ozden¹, Marianne Lucas-Hourani¹, Pierre-Emmanuel Ceccaldi¹, Ajoy Basak^¶, Menogh Valentine^¶, Suzanne Benjannet^||, Josée Hamelin^||, Yves Jacob^**, Kamel Mamchaoui, Vincent Mouly, Philippe Desprès^¶¶, Antoine Gessain, Gillian Butler-Browne, Michel Chrétien^||, Frédéric Tangy, Pierre-Olivier Vidalain², and Nabil G. Seidah^||23

From the Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes and Laboratoire de Génomique Virale et Vaccination, CNRS URA 3015, Institut Pasteur, 75724 Paris, France, the ^¶Chronic Disease Program, Regional Protein Chemistry Center, Ottawa Health Research Institute, Ottawa, Ontario K1Y 4E9, Canada, the ^||Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada, the ^**Unité postulante de Génétique, Papillomavirus et Cancer Humain, Institut Pasteur, 75724 Paris, France, the UMR S 787, Université Pierre et Marie Curie, 75634 Paris, France, U787, INSERM, Facultédemédecine Pitié-Salpétrière, 75634 Paris, France, and the ^¶¶Unité des Interactions Moléculaires Flavivirus-Hôtes, Institut Pasteur, 75724 Paris, France

Chikungunya virus (CHIKV) is a mosquito-transmitted Alphavirus that causes in humans an acute infection characterized by polyarthralgia, fever, myalgia, and headache. Since 2005 this virus has been responsible for an epidemic outbreak of unprecedented magnitude. By analogy with other alphaviruses, it is thought that cellular proteases are able to process the viral precursor protein E3E2 to produce the receptor-binding E2 protein that associates as a heterodimer with E1. Destabilization of the heterodimer by exposure to low pH allows viral fusion and infection. We show that among a large panel of proprotein convertases, membranous furin but also PC5B can process E3E2 from African CHIKV strains at the HRQRR⁶⁴ST site, whereas a CHIKV strain of Asian origin is cleaved at RRQRR⁶⁴SI by membranous and soluble furin, PC5A, PC5B, and PACE4 but not by PC7 or SKI-1. Using fluorogenic model peptides and recombinant convertases, we observed that the Asian strain E3E2 model peptide is cleaved most efficiently by furin and PC5A. This cleavage was also observed in CHIKV-infected cells and could be blocked by furin inhibitor decanoyl-RVKR-chloromethyl ketone. This inhibitor was compared with chloroquine for its ability to inhibit CHIKV spreading in myoblast cell cultures, a cell-type previously described as a natural target of this virus. Our results demonstrate the role of furin-like proteases in the processing of CHIKV particles and point out new approaches to inhibit this infection.

Received for publication, March 28, 2008 , and in revised form, June 3, 2008.

^* This work was supported in part by Canadian Institutes of Health Research Grant MOP 44363, Canada Chair Grant 201652, a grant from the Strauss foundation (to N. G. S.), and grants from the "Chikungunya" Transversal Research Program from Institut Pasteur (to S. O., M. L.-H., P.-E. C., P. D., A. G., F. T., and P.-O. V.), Association Française contre les Myopathies (to S. O., P.-E. C., G. B.-B., V. M., and K. M.), and MYORES Network of Excellence (to G. B.-B. and V. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² Both two authors contributed equally to this work.

³ To whom correspondence should be addressed: Laboratory of Biochemical Neuroendocrinology, Clinical Research Inst. of Montreal, 110 Pine Ave. West, Montreal, Quebec H2W 1R7, Canada. Fax: 514-987-5542; E-mail: seidahn{at}ircm.qc.ca.

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