An ivermectin – atorvastatin combination impairs nuclear transport inhibiting dengue infection in vitro and in vivo
Selvin Noé Palacios-Rápalo,
Carlos Noe Farfan-Morales,
Carlos Daniel Cordero-Rivera,
Luis Adrián De Jesús-González,
José Manuel Reyes-Ruiz,
Marco Antonio Meraz-Ríos,
Rosa María Del Ángel
Affiliations
Selvin Noé Palacios-Rápalo
Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City 07360, Mexico
Carlos Noe Farfan-Morales
Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City 07360, Mexico; Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana (UAM), Unidad Cuajimalpa, Ciudad de México 05348, México
Carlos Daniel Cordero-Rivera
Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City 07360, Mexico
Luis Adrián De Jesús-González
Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City 07360, Mexico; Unidad de Investigación Biomédica de Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas, Zacatecas, México
José Manuel Reyes-Ruiz
Unidad Médica de Alta Especialidad, Hospital de Especialidades No. 14, Centro Médico Nacional “Adolfo Ruiz Cortines”, Instituto Mexicano del Seguro Social (IMSS), Veracruz 91897, México; Facultad de Medicina, Región Veracruz, Universidad Veracruzana (UV), Veracruz 91700, México
Marco Antonio Meraz-Ríos
Department of Molecular Biomedicine, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City 07360, Mexico
Rosa María Del Ángel
Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City 07360, Mexico; Corresponding author
Summary: Dengue virus (DENV) uses cellular nuclear transport machinery to import some proteins into the nucleus. Recently, the non-structural protein 3 (NS3) of DENV was localized in the nucleus of infected cells; however, its nuclear import mechanism is still unknown. In this study, we demonstrate that Ivermectin (IVM) inhibits the nuclear localization of NS3 through the inhibition of the Importin α/β1 pathway. We also report that Atorvastatin (ATV) can modulate the nuclear transport of NS3 protease and NS5 polymerase of DENV-2. On the other hand, we found that IVM and ATV treatments reduce the alteration of nuclear pore complex (NPC) proteins, and an IVM+ATV combination reduced DENV infection both in vitro and in vivo. Hence, we conclude that ATV transport inhibition is an additional antiviral effect of this drug, suggesting a potential anti-DENV therapy in combination with IVM.
