(1352-A) Nuisance compound behavior in cellular assays: nonspecific membrane bilayer perturbations by ivermectin underlie SARS-CoV-2 in vitro activity
Monday, February 5, 2024
12:00 PM – 1:00 PM EST
Location: Exhibit Halls AB
Abstract: The antiparasitic drug ivermectin has been proposed as a potential host-directed antiviral agent with activity against SARS-CoV-2. The disconnect between preclinical studies and the lack of clinical efficacy in well-designed clinical trials remains a puzzle so, to examine the potential for ivermectin to be repurposed as an antiviral agent, we undertook a series of preclinical studies to elucidate the mechanism(s) underlying its antiviral activity. 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 the concentrations where ivermectin reduced viral burden it also decreased cell viability and increased biomarkers of cytotoxicity and apoptosis. Further mechanistic and profiling studies revealed that ivermectin is a potent modifier of membrane bilayers at the concentrations where it decreases the SARS-CoV-2 viral burden, resulting in nonspecific bilayer-mediated dysregulation of membrane protein function—including modulation of G-protein coupled receptors and ion channels. Structure-activity studies show that the antiviral, cytotoxic, and membrane perturbation effects overlap. Taken together, these results indicate that the primary molecular mechanism for the in vitro antiviral activity of ivermectin is likely nonspecific membrane perturbation (in contrast to immediate lysis) and rationalize at the molecular level why ivermectin is not translatable into an effective antiviral agent. These results and experimental workflow provide a paradigm for performing preclinical studies on (pandemic-related) drug repurposing. Considering the expected incidence of this mechanism, they further highlight the importance of testing bioactive compounds for membrane bilayer perturbation.