Extracellular Disintegration of Viral Proteins as an Innovative Strategy for Developing Broad-Spectrum Antivirals Against Coronavirus

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has claimed millions of lives and caused innumerable economic losses worldwide. Unfortunately, state-of-the-art treatments still lag behind the continual emergence of new variants. Key to resolving this issue is developing antivirals to deactivate coronaviruses regardless of their structural evolution. Here, we report an innovative antiviral strategy involving extracellular disintegration of viral proteins with hyperanion-grafted enediyne (EDY) molecules. The core EDY generates reactive radical species and causes significant damage to the spike protein of coronavirus, while the hyperanion groups ensure negligible cytotoxicity of the molecules. The EDYs exhibit antiviral activity down to nanomolar concentrations, and the selectivity index of up to 20,000 against four kinds of human coronavirus, including the SARS-CoV-2 Omicron variant, suggesting the high potential of this new strategy in combating the COVID-19 pandemic and a future "disease X."

Rapid and Repetitive Inactivation of SARS‐CoV‐2 and Human Coronavirus on Self‐Disinfecting Anionic Polymers

While the ongoing COVID‐19 pandemic affirms an urgent global need for effective vaccines as second and third infection waves are spreading worldwide and generating new mutant virus strains, it has also revealed the importance of mitigating the transmission of SARS‐CoV‐2 through the introduction of restrictive social practices. Here, it is demonstrated that an architecturally‐ and chemically‐diverse family of nanostructured anionic polymers yield a rapid and continuous disinfecting alternative to inactivate coronaviruses and prevent their transmission from contact with contaminated surfaces. Operating on a dramatic pH‐drop mechanism along the polymer/pathogen interface, polymers of this archetype inactivate the SARS‐CoV‐2 virus, as well as a human coronavirus surrogate (HCoV‐229E), to the minimum detection limit within minutes. Application of these anionic polymers to frequently touched surfaces in medical, educational, and public‐transportation facilities, or personal protection equipment, can provide rapid and repetitive protection without detrimental health or environmental complications.

Macromolecular Viral Entry Inhibitors as Broad-Spectrum First-Line Antivirals with Activity against SARS-CoV-2.

Inhibitors of viral cell entry based on poly(styrene sulfonate) and its core-shell nanoformulations based on gold nanoparticles are investigated against a panel of viruses, including clinical isolates of SARS-CoV-2. Macromolecular inhibitors are shown to exhibit the highly sought-after broad-spectrum antiviral activity, which covers most analyzed enveloped viruses and all of the variants of concern for SARS-CoV-2 tested. The inhibitory activity is quantified in vitro in appropriate cell culture models and for respiratory viral pathogens (respiratory syncytial virus and SARS-CoV-2) in mice. Results of this study comprise a significant step along the translational path of macromolecular inhibitors of virus cell entry, specifically against enveloped respiratory viruses.

Polycations and polyanions in SARS-CoV-2 infection.

We hypothesize that polycations, such as nuclear histones, released by neutrophils COVID-19 aggravate COVID-19 by multiple mechanisms: (A) Neutralization of the electrostatic repulsion between the virus particles and the cell membrane, thereby enhancing receptor-mediated entry. (B) Binding to the virus particles, thereby inducing opsonin-mediated endocytosis. (C) Adding to the cytotoxicity, in conjunction with oxidants, cytokines and other pro-inflammatory substances secreted by cells of the innate immunity system. These effects may be alleviated by the administration of negatively charged polyanions such as heparins and heparinoids.