Inhibition of Chikungunya virus infection in cultured human muscle cells by furin inhibitors: Impairment of the maturation of the E2 surface glycoprotein
Autor(es): Ozden Simona, Lucas-Hourani Marianne, Ceccaldi Pierre-Emmanuel, Basak Ajoy, Valentine Menogh, Benjannet Suzanne, Hamelin Josée, Jacob Yves, Mamchaoui Kamel, Mouly Vincent, Desprès Philippe, Gessain Antoine, Butler-Browne Gillian, Chrétien Michel, Tangy Frédéric, Vidalain Pierre-Olivier, Seidah Nabil G
Resumo: Chikungunya virus (CHIKV) is a mosquito-transmitted Alphavirus that causes in humans an acute infection characterized by polyarthralgia, fever, myalgia, - 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 - 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 HRQRR(64) / ST site, whereas a CHIKV strain of Asian origin is cleaved at RRQRR(64) / SI by membranous - soluble furin, PC5A, PC5B, - PACE4 but not by PC7 or SKI-1. Using fluorogenic model peptides - recombinant convertases, we observed that the Asian strain E3E2 model peptide is cleaved most efficiently by furin - PC5A. This cleavage was also observed in CHIKV-infected cells - 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 - point out new approaches to inhibit this infection.
Imprenta: The Journal of Biological Chemistry, v. 283, n. 32, p. 21899-21908, 2008
Identificador do objeto digital: 10.1074/jbc.M802444200
Descritores: Chikungunya virus - Biosynthesis ; Chikungunya virus - Cell ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Protein synthesis ; Chikungunya virus - Proteins ; Chikungunya virus - Viral infections ; Chikungunya Virus - Virus ; Chikungunya virus - Chikungunya fever ; Chikungunya virus - Epidemic
Data de publicação: 2008
