Abstract: Has Ivermectin Virus-Directed Effects against SARS-CoV-2? Rationalizing the Action of a Potential Multitarget Antiviral Agent Antonio Francés-Monerris,1,2,* Cristina García-Iriepa,3,4,* Isabel Iriepa,4,5 Cécilia Hognon,1 Tom Miclot,1,6 Giampaolo Barone,6 Antonio Monari,1,* and Marco Marazzi3,4,* 1 Université de Lorraine and CNRS, LPCT UMR 7019, F-54000 Nancy, France. 2 Departament de Química Física, Universitat de València, 46100 Burjassot, Spain. 3 Department of Analytical Chemistry, Physical Chemistry and Chemical Engineering, Universidad de Alcalá, Ctra. Madrid-Barcelona, Km 33,600, 28871 Alcalá de Henares, Madrid, Spain. 4 Chemical Research Institute “Andrés M. del Río” (IQAR), Universidad de Alcalá, 28871 Alcalá de Henares, Madrid, Spain. 5 Department of Organic and Inorganic Chemistry, Universidad de Alcalá, Ctra. Madrid-Barcelona, Km 33,600, 28871 Alcalá de Henares, Madrid, Spain. 6 Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Università degli Studi di Palermo, Viale delle Scienze, 90128 Palermo, Italy. *A. F.-M.: antonio.frances@uv.es, C. G.-I.: cristina.garciai@uah.es, A. M.: Antonio.monari@univ-lorraine.fr, M. M.: marco.marazzi@uah.es Supporting information for this article is given via a link at the end of the document. that have required the implementation of severe social distancing measures and movement restrictions, including full lock-down, causing significant social and economic damage. In this context of emergency, the international scientific community is reacting with rapid responses to enhance the knowledge of the virus’s fundamental processes and hence facilitate the control of the pandemic. This includes a very rapid sequencing of SARS-CoV-2 genome, solving the structures of key viral proteins, modeling of the pandemic spread to assist public decision, and developing better detection tests,[4] vaccines,[5] and effective treatments.[6] Due to the urgency posed by the pandemic, an efficient and relatively fast strategy to obtain suitable therapeutic agents consists in exploring the antiSARS-CoV-2 activity of drugs already approved for human use,[7] in a drug repurposing framework. Since the safety profiles of the candidates are well known, only the antiviral efficacy remains to be assessed, thus strongly reducing the time required for clinical tests and approval. A drug that has shown promising results is the broad-spectrum antiparasitic ivermectin (Figure 1), which has been shown to inhibit SARS-CoV-2 replication in cell cultures with an IC50 of ~2 μM.[8] In particular, the action of ivermectin results in 99.8% reduction of cell associated viral RNA in 24 hours, while a ~5000fold decrease of the viral RNA content is observed after 48 hours with a maintaining of the effect at 72 hours. Recently, Yang et al[9] have shown that ivermectin is a host-directed agent, i.e. the main targets of the drug are not in the pathogen but in the host cell. This is coherent with the broad antiviral activity observed against HIV, influenza, dengue virus, Zika, and other flaviviruses.[10] Ivermectin inhibits the transport of viral proteins into cellular nuclei mediated by importin α/β1 carriers, an import process related to the suppression of the host immune response by impairing mRNA function.[9] This pathogen-independent mechanism suggests that only very low concentrations of ivermectin could be sufficient to control SARS-CoV-2 infection.[11] A recent report have questioned that the plasma..