title: Antiviral activities of selected antimalarials against dengue virus type 2 and Zika virus.
abstract: In a previous study, twelve antimalarial compounds, amodiaquine (AQ) and derivatives, were shown to have potent anti-dengue viral (DENV) activity by using the stable DENV2 Renilla luciferase reporter replicon expressing BHK-21 cells, infectivity (plaque), and the qRT-PCR assays. In this study, we performed molecular modeling on these compounds to determine their stereo-electronic properties required for optimal antiviral activity. Based on the similarity of calculated stereo-electronic profiles, specifically the electrostatic potential profiles of the compounds, and in silico screening of related compounds from literature, we identified three additional compounds, Quinacrine (QC), Mefloquine (MQ), and GSK369796. Analysis of their antiviral activities indicated that all three compounds have high anti-DENV activity in the DENV2 replicon expressing cells with EC50values of 5.30 ± 1.31 μM (QC), 3.22 ± 0.37 μM (MQ), and 5.06 ± 0.86 μM (GSK369796). The infectivity assays revealed the EC50values of 7.09 ± 1.67 μM (QC), 4.36 ± 0.31 μM (MQ) and 3.03 ± 0.35 μM (GSK369796). The mode of action of these compounds is through inhibition of autophagy, thereby affecting DENV2 replication. Moreover, these compounds also showed antiviral activity against the rapidly emerging Zika virus (ZIKV) with EC50values of 2.27 ± 0.14 μM (QC), 3.95 ± 0.21 μM (MQ), and 2.57 ± 0.09 μM (GSK369796).
authors.affiliation: Department of Microbiology & Immunology, Georgetown University School of Medicine, Washington DC, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Balasubramanian
authors.affiliation: Department of Microbiology & Immunology, Georgetown University School of Medicine, Washington DC, USA.
authors.forename: Tadahisa
authors.initials: T
authors.lastname: Teramoto
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Howard University, Washington DC, USA.
authors.forename: Amol A
authors.initials: AA
authors.lastname: Kulkarni
authors.affiliation: Department of Microbiology & Immunology, Georgetown University School of Medicine, Washington DC, USA. Electronic address: ab3094@georgetown.edu.
authors.forename: Apurba K
authors.initials: AK
authors.lastname: Bhattacharjee
authors.affiliation: Department of Microbiology & Immunology, Georgetown University School of Medicine, Washington DC, USA. Electronic address: rp55@georgetown.edu.
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Padmanabhan
mesh_terms: D000655:Amodiaquine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D003198:Computer Simulation; D003716:Dengue Virus / Q000187:drug effects* / Q000502:physiology; D055808:Drug Discovery; D006801:Humans; D015767:Mefloquine / Q000737:chemistry / Q000494:pharmacology; D011796:Quinacrine / Q000737:chemistry / Q000494:pharmacology; D012093:Replicon / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D000071244:Zika Virus / Q000187:drug effects* / Q000502:physiology
chemical_list: D000962:Antimalarials; D000998:Antiviral Agents; C540176:N-tert-butylisoquine; D000655:Amodiaquine; D011796:Quinacrine; D015767:Mefloquine
keywords: Autophagy; Cathepsin B; In silico modeling; Molecular electrostatic potentials (MEPs); Renilla luciferase reporter replicon; Stereo-electronic profiles