title: Suramin inhibits chikungunya virus replication through multiple mechanisms.
abstract: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes severe and often persistent arthritis. In recent years, millions of people have been infected with this virus for which registered antivirals are still lacking. Using our recently established in vitro assay, we discovered that the approved anti-parasitic drug suramin inhibits CHIKV RNA synthesis (IC50 of ∼5μM). The compound inhibited replication of various CHIKV isolates in cell culture with an EC50 of ∼80μM (CC50>5mM) and was also active against Sindbis virus and Semliki Forest virus. In vitro studies hinted that suramin interferes with (re)initiation of RNA synthesis, whereas time-of-addition studies suggested it to also interfere with a post-attachment early step in infection, possibly entry. CHIKV (nsP4) mutants resistant against favipiravir or ribavirin, which target the viral RNA polymerase, did not exhibit cross-resistance to suramin, suggesting a different mode of action. The assessment of the activity of a variety of suramin-related compounds in cell culture and the in vitro assay for RNA synthesis provided more insight into the moieties required for antiviral activity. The antiviral effect of suramin-containing liposomes was also analyzed. Its approved status makes it worthwhile to explore the use of suramin to prevent and/or treat CHIKV infections.
authors.affiliation: Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Irina C
authors.initials: IC
authors.lastname: Albulescu
authors.affiliation: Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marcella
authors.initials: M
authors.lastname: van Hoolwerff
authors.affiliation: Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Wolters
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bottaro
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Nastruzzi
authors.affiliation: Department of Chemistry and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Shih Chi
authors.initials: SC
authors.lastname: Yang
authors.affiliation: Department of Chemistry and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Shwu-Chen
authors.initials: SC
authors.lastname: Tsay
authors.affiliation: Department of Chemistry and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Jih Ru
authors.initials: JR
authors.lastname: Hwu
authors.affiliation: Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Snijder
authors.affiliation: Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: M.J.van_Hemert@lumc.nl.
authors.forename: Martijn J
authors.initials: MJ
authors.lastname: van Hemert
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002646:Chikungunya virus / Q000187:drug effects* / Q000502:physiology*; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D012672:Semliki forest virus / Q000187:drug effects; D012845:Sindbis Virus / Q000187:drug effects; D013498:Suramin / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D013498:Suramin
keywords: Alphavirus; Chikungunya virus; Entry; Inhibitor; RNA synthesis; Suramin