title: Antibody-dependent enhancement of dengue virus infection is inhibited by SA-17, a doxorubicin derivative.
abstract: Antibody-dependent enhancement (ADE) is thought to play a critical role in the exacerbation of dengue virus (DENV)-induced disease during a heterologous re-infection. Despite ADE's clinical impact, only a few antiviral compounds have been assessed for their anti-ADE activity. We reported earlier that SA-17, a doxorubicin derivative, efficiently inhibits the in vitro infection of DENV and yellow fever virus. Here we explored SA-17's mechanism of inhibition and investigated if the compound is active against ADE of DENV infection. Since enhanced infectivity stimulated by antibodies has been observed with standard and immature DENV, both types of virions were included in the study. We observed that SA-17 (i) inhibits DENV infection by preventing binding/entry to the cell and (ii) interferes with antibody-mediated infection of both standard and immature DENV2. SA-17 markedly reduced the infectivity of DENV2 in ADE conditions, with IC50s ranging from 0.26 to 2.89μM. The compound exerted its activity when added before, during, and after antibody-opsonization of standard and immature virus. Thus, molecules with the characteristics of SA-17 may be attractive antiviral agents since they can be used both to block DENV2 entry during primary and secondary infection and to inhibit ADE of standard and immature virus.
authors.affiliation: Department of Medical Microbiology, Molecular Virology Section, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
authors.forename: Nilda V
authors.initials: NV
authors.lastname: Ayala-Nuñez
authors.forename: Patsaporn
authors.initials: P
authors.lastname: Jarupathirun
authors.forename: Suzanne J F
authors.initials: SJ
authors.lastname: Kaptein
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.forename: Jolanda M
authors.initials: JM
authors.lastname: Smit
mesh_terms: D000914:Antibodies, Viral / Q000276:immunology; D019067:Antibody-Dependent Enhancement / Q000187:drug effects*; D000998:Antiviral Agents / Q000494:pharmacology*; D003715:Dengue / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D003716:Dengue Virus / Q000187:drug effects* / Q000502:physiology; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000914:Antibodies, Viral; D000998:Antiviral Agents; D004317:Doxorubicin
keywords: Antibody-dependent enhancement; Dengue virus; Doxorubicin derivative