Nonspecific membrane bilayer perturbations by ivermectin underlie SARS-CoV-2 in vitro activity.

Autor:	Eastman RT; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Rusinova R; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA., Herold KF; Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA., Huang XP; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.; National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina School of Medicine, Chapel Hill, NC, USA., Dranchak P; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Voss TC; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Rana S; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Shrimp JH; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., White AD; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA., Hemmings HC Jr; Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA.; Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA., Roth BL; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.; National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina School of Medicine, Chapel Hill, NC, USA.; Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC, USA., Inglese J; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.; Metabolic Medicine Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA., Andersen OS; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA., Dahlin JL; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Oct 24. Date of Electronic Publication: 2023 Oct 24.
DOI:	10.1101/2023.10.23.563088
Abstrakt:	Since it was proposed as a potential host-directed antiviral agent for SARS-CoV-2, the antiparasitic drug ivermectin has been investigated thoroughly in clinical trials, which have provided insufficient support for its clinical efficacy. To examine the potential for ivermectin to be repurposed as an antiviral agent, we therefore undertook a series of preclinical studies. Consistent with early reports, ivermectin decreased SARS-CoV-2 viral burden in in vitro models at low micromolar concentrations, five- to ten-fold higher than the reported toxic clinical concentration. At similar concentrations, ivermectin also decreased cell viability and increased biomarkers of cytotoxicity and apoptosis. Further mechanistic and profiling studies revealed that ivermectin nonspecifically perturbs membrane bilayers at the same concentrations where it decreases the SARS-CoV-2 viral burden, resulting in nonspecific modulation of membrane-based targets such as G-protein coupled receptors and ion channels. These results suggest that a primary molecular mechanism for the in vitro antiviral activity of ivermectin may be nonspecific membrane perturbation, indicating that ivermectin is unlikely to be translatable into a safe and effective antiviral agent. These results and experimental workflow provide a useful paradigm for performing preclinical studies on (pandemic-related) drug repurposing candidates. Competing Interests: Conflicting interests JLD is currently an employee of Agios Pharmaceuticals. RTE is currently an employee of Novartis Pharmaceuticals. The remaining authors hereby declare no conflicting interests pertaining to the material in this manuscript.
Databáze:	MEDLINE
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