Anti-infectives (Track)

INTERACTION BETWEEN THE VIRAL ENVELOPEPROTEIN AND HEPARAN SULFATE PROTEOGLYCANS AS TARGET FOR DENGUE VIRUS INHIBITORS

Peter Vervaeke, Sam Noppen, Vincent Vanheule, Anneleen Mortier, Pasqua Oreste, PaulProost and Sandra Liekens

Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium and Glycores 2000 S.r.l., Milan, Italy

Abstract

Dengue is the most prevalent mosquito-borne viral disease in humans. Currently, 3.9 billion people are at risk of dengue in more than 100 countries in tropical and subtropical regions worldwide. It is estimated that 390 million infections occur each year, including 500,000 severe cases and 25,000 deaths. As such, DENV has a major impact on global health system, economies and populations. Dengue is caused by any of the four closely related dengue virus serotypes (DENV 1-4) and the disease spectrum ranges from a self-limiting febrile illness called dengue fever (DF) to the severe, and potentially life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), which are characterized by thrombocytopenia, increased vascular permeability (and subsequent plasma leakage) and organ impairment. Currently no vaccine or antiviral drugs are available to prevent or treat DENV infections. The primary target cells for DENV infection and replication in vivo are dendritic cells, monocytes and macrophages. The extent to which endothelial cells (ECs), which line the inner layer of the endothelium and present the primary fluid barrier of the vasculature, contribute to dengue pathogenesis remains elusive. We found that DENV productively infects human microvascular ECs and that DENV infection of ECs results in the strong upregulation of inflammatory and permeability-inducing cytokines, involved in dengue pathogenesis. DENV infection of ECs was shown to be mediated by heparan sulfate proteoglycans (HSPGs) on the surface of ECs. Therefore, we evaluated two classes of compounds for their anti-DENV potency: (i) HS mimetics and (ii) competitive binders to HS. We showed that derivatives of the K5 polysaccharide of E. coli (HS mimetics) as well as highly basic chemokine peptides (competitive binders) inhibit virus attachment to, and replication in, microvascular ECs by interfering with the binding of the DENV envelope (E) protein to HSPGs. Our results indicate that direct infection of microvascular ECs by DENV may contribute to DENV pathogenesis and that the interaction between DENV and HSPGs may serve as an attractive antiviral target.