Researchers analyze potential of niclosamide as a SARS-CoV-2 🦠 treatment SARSCoV2 Coronavirus Disease COVID biorxivpreprint UMich
Diagram of niclosamides effect on SARS-CoV-2 entry and spike protein-mediated syncytia formation. 1.) SARS-CoV-2 binds to the ACE2 receptor of the host cell and enters. Niclosamide has been shown to inhibit this entry step in vitro 2.) Viral replication generates many copies of the RNA genome. 3.) Infection results in an increased expression of viral spike protein and host cell TMEM16F at the plasma membrane. 4.
Nonetheless, there are various potential drawbacks to using niclosamide in COVID-19. These drawbacks included high cellular toxicity, significant polypharmacology, low bioavailability, and uncertain efficacy of niclosamide against arising SARS-CoV-2 variants of concern . In addition, in VeroE6 cells, the authors assessed niclosamide's effectiveness against the SARS-CoV-2 Alpha , wild type , Beta , Gamma , and Delta variants. Finally, they examined the impact of niclosamide therapy on COVID-19 using the morphological characterization of VeroE6 cells infected with Alpha to determine the mechanism of action .
Despite encouraging preliminary results, the authors demonstrated that niclosamide has a poor in vitro selectivity index for inhibiting SARS-CoV-2 since its antiviral activity coincides with its cytotoxicity. They further show that niclosamide's effectiveness against the SARS-CoV-2 VOCs varies greatly, ranging from 298 nM for the Beta variant to 1664 nM for the wildtype and that it was particularly effective against variants with greater cell-to-cell spread, such as Alpha.
Furthermore, the current structure-activity examination uncovered certain mechanistic aspects of niclosamide. Most importantly, following the removal of the hydroxyl group of protonophore, both cell models employed in this study stopped functioning. This inference indicated that nonspecific endolysosomal neutralization was the major MOA.
The researchers pointed out that longer niclosamide exposures at effective anti-SARS-CoV-2 concentrations probably result in noticeable side effects, which restricts practical use. Hence, the safety of niclosamide at antiviral titers in vivo needs further investigation.
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