Work

Evaluating Molecular Mechanism of Viral Inhibition of Aerosolized Smart Nano-Enabled Antiviral Therapeutic (SNAT) on SARS-CoV-2-Infected Hamsters

Year: 2024

Type: article

Abstract: Purpose: Smart Nano-enabled Antiviral Therapeutic (SNAT) is a promising nano-drug that previously demonstrated efficacy in preclinical studies to alleviate SARS-CoV-2 pathology in hamsters. SNAT is comprised of taxoid (Tx)-decorated amino (NH2)-functionalized near-atomic size positively charged silver nanoparticles (Tx–[NH2-AgNPs]). Herein, we aimed to elucidate the molecular mechanism of viral inhibition and safety of aerosolized SNAT treatment in SARS-CoV-2 infected hamsters using complementary biophysical and molecular techniques.Methods: HR-TEM and EDS analyses were used to investigate electrostatic interactions between SNAT and intact SARS-CoV-2. ELISA was used to confirm interactions between SNAT and SARS-CoV-2 encoded S protein and its subunits. In vitro SARS-CoV-2 infected Calu-3 cells were used to determine if different concentrations of SNAT could lower viral infectivity. Extraction-free whole transcriptome assay was used to detect changes in circulatory micronome in golden Syrian hamsters treated with two doses of intranasally delivered SNAT (10 µg/ml of 2 ml each administered 24 h apart). Targets of upregulated and downregulated miRNA were investigated using miRBD, and physiologically relevant targets were verified using IHC and western blotting.Results: HR-TEM coupled with EDS and ELISA analyses showed SNAT binds to the SARS-CoV-2 virus by interacting with intact spike (S) protein and its S2 subunit. SNAT treatment ≥ 0.001 mg/ml significantly lowered SARS-CoV-2 infections of Calu-3 cells. Uninfected hamsters treated with SNAT had altered circulatory concentrations of 18 miRNAs (8 miRNAs upregulated, 10 downregulated) on day 3 post-treatment compared to uninfected controls. SNAT-induced downregulation of miR-141-3p and miR-200b-3p can reduce viral replication and inflammation by targeting Ythdf2 and Slit2, respectively. Further, SNAT treatment significantly lowered IL-6 expression in infected hamster lungs compared to untreated infected hamsters.Conclusion: We demonstrate that SNAT binds directly to SARS-CoV-2 particles via the S protein to prevent viral entry and propose a model by which SNAT alters the cellular milieu to promote antiviral cellular processes and neutralize infection. Our results provide promising insights into the use of low-dose SNAT in treating SARS-CoV-2 infections.

Source: Toxics

DOI: 10.3390/toxics12070495