A trifunctional peptide broadly inhibits SARS-CoV-2 Delta and Omicron variants in hamsters

Abstract

The emergence of highly transmissible SARS-CoV-2 variants has led to the waves of the resurgence of COVID-19 cases. Effective antivirals against variants are required. Here we demonstrate that a human-derived peptide 4H30 has broad antiviral activity against the ancestral virus and four Variants of Concern (VOCs) in vitro. Mechanistically, 4H30 can inhibit three distinct steps of the SARS-CoV-2 life cycle. Specifically, 4H30 blocks viral entry by clustering SARS-CoV-2 virions; prevents membrane fusion by inhibiting endosomal acidification; and inhibits the release of virions by cross-linking SARS-CoV-2 with cellular glycosaminoglycans. In vivo studies show that 4H30 significantly reduces the lung viral titers in hamsters, with a more potent reduction for the Omicron variant than the Delta variant. This is likely because the entry of the Omicron variant mainly relies on the endocytic pathway which is targeted by 4H30. Moreover, 4H30 reduces syncytia formation in infected hamster lungs. These findings provide a proof of concept that a single antiviral can inhibit viral entry, fusion, and release.

Human surfactant protein A inhibits SARS-CoV-2 infectivity and alleviates lung injury in a mouse infection model

“…We next assessed the biological significance of SP-A binding with SARS-CoV-2 S protein by pre-incubating pseudotyped and infectious SARS-CoV-2 (Delta) with SP-A before cellular challenge. The delta variant was used for this experiment and in our infectivity assays because of the profound pathogenesis induced by this variant both in the human population and in in vitro and in vivo models of infection ( 37 – 39 ). In examining the early events that occur upon SP-A interaction with SARS-CoV-2, we have uncovered that SP-A binding to SARS-CoV-2 RBD can impair viral binding and entry in lung epithelial cells, ultimately resulting in low viral load in cells.…”

Human Surfactant Protein A Alleviates SARS-CoV-2 Infectivity in Human Lung Epithelial Cells

“…We next assessed the biological significance of SP-A binding with SARS-CoV-2 S protein by pre-incubating pseudotyped and infectious SARS-CoV-2 (Delta) with SP-A before cellular challenge. The delta variant was used for this experiment and in our infectivity assays because of the profound pathogenesis induced by this variant both in the human population and in in vitro and in vivo models of infection (29)(30)(31). In examining the early events that occur upon SP-A interaction with SARS-CoV-2, we have uncovered that SP-A binding to SARS-CoV-2 RBD can impair viral binding and entry in lung epithelial cells, ultimately resulting in low viral load in cells.…”

Peptidic defective interfering gene nanoparticles against Omicron, Delta SARS-CoV-2 variants and influenza A virus in vivo

“…Tissues were processed for anti-nucleocapsid assay. Tissue slides were blocked by Sudan Black B and 1% BSA at room temperature for 1 h. Slides were incubated with rabbit IgG anti-NP (1:1000) 51 at room temperature for overnight at 4 °C and then washed by PBS and then incubated with goat anti-rabbit IgG Alexa-488 (Life Technologies, Cat # A32731, 1:200) at room temperature for 30 min. Finally, slides were washed by PBS and incubated with DAPI for nucleus staining.…”