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Review of "Nonspecific Membrane Bilayer Perturbations by Ivermectin Underlie SARS-CoV-2 in Vitro Activity"

Reviewers: S Einav & M Mishra (Stanford) | 📗📗📗📗◻️

Published onJul 01, 2024
Review of "Nonspecific Membrane Bilayer Perturbations by Ivermectin Underlie SARS-CoV-2 in Vitro Activity"
key-enterThis Pub is a Review of
Nonspecific membrane bilayer perturbations by ivermectin underlie SARS-CoV-2 in vitro activity
Nonspecific membrane bilayer perturbations by ivermectin underlie SARS-CoV-2 in vitro activity
Description

Abstract 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.

To read the original manuscript, click the link above.

Summary of Reviews: The reviewer found the study reliable, providing evidence against the translational potential of ivermectin for COVID-19 treatment. While the experiments were well-designed and controlled, the reviewer noted that the overall impact and novelty were limited, as similar conclusions could have been drawn from existing data. They highlighted the importance of communicating these findings to guide drug discovery and clinical trial prioritization. The reviewer suggested improvements, including clearer messaging on screening workflows and additional specificity tests. They emphasized the need for more careful study and prioritization of drug candidates for repurposing as antivirals before proceeding to clinical trials.

Reviewer 1 (Shirit E… & Manjari M…) | 📗📗📗📗◻️

RR:C19 Strength of Evidence Scale Key

📕 ◻️◻️◻️◻️ = Misleading

📙📙 ◻️◻️◻️ = Not Informative

📒📒📒 ◻️◻️ = Potentially Informative

📗📗📗📗◻️ = Reliable

📘📘📘📘📘 = Strong

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