Low Selectivity Indices of Ivermectin and Macrocyclic Lactones on SARS-CoV-2 Replication In Vitro

Christine Chable-Bessia,Cédric Chesnais,Alain Makinson,Sébastien Lyonnais,Nathalie Gros,Jitendriya Swain,Aymeric Neyret,Charlotte Boullé,Peggy Merida,Delphine Muriaux,Mathilde Hénaut

doi:10.3390/covid2010005

Abstract

Ivermectin was first approved for human use as an endectocide in the 1980s. It remains one of the most important global health medicines in history and has recently been shown to exert in vitro activity against SARS-CoV-2. However, the macrocyclic lactone family of compounds has not previously been evaluated for activity against SARS-CoV-2. The present study aims at comparing their anti-viral activity in relevant human pulmonary cell lines in vitro. Here, in vitro antiviral activity of the avermectins (ivermectin and selamectin) and milbemycins (moxidectin and milbemycin oxime) were assessed against a clinical isolate from a CHU Montpellier patient infected with SARS-CoV-2 in 2020. Ivermectin, like the other macrocyclic lactones moxidectin, milbemycin oxime and selamectin, reduced SARS-CoV-2 replication in vitro (EC50 of 2–5 μM). Immunofluorescence assays with ivermectin and moxidectin showed a reduction in the number of infected and polynuclear cells, suggesting a drug action on viral cell fusion. However, cellular toxicity of the avermectins and milbemycins during infection showed a very low selectivity index of <10. Thus, none of these agents appears suitable for human use for its anti-SARS-CoV-2 activity per se, due to low selectivity index.

Highlights

Introduction iationsIn December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)emerged in Wuhan, China [1,2]
To determine if avermectins or milbemycins could protect cells from SARS-CoV-2 infection and to evaluate their toxicity, a cytopathic effect (CPE) reduction assay was first performed on African green monkey kidney-derived cell line Vero E6, which presents an
Our data show that DOR, MIL and SEL are not clinically relevant candidates. They are not approved for human use and should not be used, and there is no rationale in our data to conduct the extensive studies that this would require

Summary

Introduction

In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Emerged in Wuhan, China [1,2]. SARS-CoV-2 is a betacoronavirus, which are enveloped viruses containing single-strand, positive-sense RNA. No effective treatment or treatment regimen has been established for coronavirus disease-2019 (COVID-19) to date and success has been achieved with vaccination modalities, there remains a need for therapeutic approaches for the unvaccinated and for vaccine escape mutants. Regulatory approved medicines for potential activity against SARS-CoV-2 offers the potential to reduce unnecessary animal and clinical evaluations. Repurposing requires a comprehensive understanding of the pharmacokinetic/pharmacodynamic relationship of the product and changes from the approved posology result in potentially significant data generation requirements. Several candidates have emerged from this strategy,

Methods

Results

Conclusion