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

doi:10.1016/j.isci.2023.108294

An ivermectin - atorvastatin combination impairs nuclear transport inhibiting dengue infection in vitro and in vivo

iScience. 2023 Oct 27;26(12):108294. doi: 10.1016/j.isci.2023.108294. eCollection 2023 Dec 15.

Authors

Selvin Noé Palacios-Rápalo¹, Carlos Noe Farfan-Morales^{1

2}, Carlos Daniel Cordero-Rivera¹, Luis Adrián De Jesús-González^{1

3}, José Manuel Reyes-Ruiz^{4

5}, Marco Antonio Meraz-Ríos⁶, Rosa María Del Ángel¹

Affiliations

¹ Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City 07360, Mexico.
² Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana (UAM), Unidad Cuajimalpa, Ciudad de México 05348, México.
³ Unidad de Investigación Biomédica de Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas, Zacatecas, México.
⁴ 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.
⁵ Facultad de Medicina, Región Veracruz, Universidad Veracruzana (UV), Veracruz 91700, México.
⁶ Department of Molecular Biomedicine, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City 07360, Mexico.

Abstract

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.

Keywords: Cell biology; Molecular biology; Parasitology; Pharmacology; Virology.