ABSTRACT
There is an unmet clinical need to end the COVID-19 pandemic. In the past 2 years, the SARS-CoV-2 continued to evolve and poses a critical challenge to the efficacy of the vaccine and neutralizing antibody therapies. The fifth wave of the pandemic is driven by the Omicron variants, due to their ability to evade prior immunity and their resistance to therapeutic antibodies. The report by Zhang et al in the current issue of EMBO Molecular Medicine shows that the engineered decoy ACE2 can reduce lung injury and improve survival in K18-hACE2 transgenic mice inoculated with a lethal dose of the SARS-CoV-2 and potentially targets the Omicron variant.
Subject(s)
COVID-19 , SARS-CoV-2 , Mice , Animals , Humans , COVID-19/therapy , Spike Glycoprotein, Coronavirus/genetics , Pandemics , Antibodies, Neutralizing/therapeutic use , Mice, Transgenic , Antibodies, ViralABSTRACT
The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants has altered the trajectory of the COVID-19 pandemic and raised some uncertainty on the long-term efficiency of vaccine strategy. The development of new therapeutics against a wide range of SARS-CoV-2 variants is imperative. We, here, have designed an inhalable siRNA, C6G25S, which covers 99.8% of current SARS-CoV-2 variants and is capable of inhibiting dominant strains, including Alpha, Delta, Gamma, and Epsilon, at picomolar ranges of IC50 in vitro. Moreover, C6G25S could completely inhibit the production of infectious virions in lungs by prophylactic treatment, and decrease 96.2% of virions by cotreatment in K18-hACE2-transgenic mice, accompanied by a significant prevention of virus-associated extensive pulmonary alveolar damage, vascular thrombi, and immune cell infiltrations. Our data suggest that C6G25S provides an alternative and effective approach to combating the COVID-19 pandemic.
Subject(s)
COVID-19 , Animals , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Pandemics , RNA, Small Interfering/genetics , SARS-CoV-2/geneticsABSTRACT
A metal nanoparticle composite, namely TPNT1, which contains Au-NP (1 ppm), Ag-NP (5 ppm), ZnO-NP (60 ppm) and ClO2 (42.5 ppm) in aqueous solution was prepared and characterized by spectroscopy, transmission electron microscopy, dynamic light scattering analysis and potentiometric titration. Based on the in vitro cell-based assay, TPNT1 inhibited six major clades of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with effective concentration within the range to be used as food additives. TPNT1 was shown to block viral entry by inhibiting the binding of SARS-CoV-2 spike proteins to the angiotensin-converting enzyme 2 (ACE2) receptor and to interfere with the syncytium formation. In addition, TPNT1 also effectively reduced the cytopathic effects induced by human (H1N1) and avian (H5N1) influenza viruses, including the wild-type and oseltamivir-resistant virus isolates. Together with previously demonstrated efficacy as antimicrobials, TPNT1 can block viral entry and inhibit or prevent viral infection to provide prophylactic effects against both SARS-CoV-2 and opportunistic infections.
Subject(s)
Gold/pharmacology , Influenza A Virus, H1N1 Subtype/physiology , Influenza A Virus, H5N1 Subtype/physiology , SARS-CoV-2/physiology , Silver/pharmacology , Zinc Oxide/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Drug Resistance, Viral/drug effects , Food Additives/pharmacology , Gold/chemistry , HEK293 Cells , Humans , Influenza A Virus, H1N1 Subtype/drug effects , Influenza A Virus, H5N1 Subtype/drug effects , Metal Nanoparticles/chemistry , Nanocomposites/chemistry , Oseltamivir/pharmacology , Particle Size , Protein Binding/drug effects , SARS-CoV-2/drug effects , Silver/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects , Zinc Oxide/chemistryABSTRACT
To circumvent the devastating pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, a humanized decoy antibody (ACE2-Fc fusion protein) was designed to target the interaction between viral spike protein and its cellular receptor, angiotensin-converting enzyme 2 (ACE2). First, we demonstrated that ACE2-Fc could specifically abrogate virus replication by blocking the entry of SARS-CoV-2 spike-expressing pseudotyped virus into both ACE2-expressing lung cells and lung organoids. The impairment of viral entry was not affected by virus variants, since efficient inhibition was also observed in six SARS-CoV-2 clinical strains, including the D614G variants which have been shown to exhibit increased infectivity. The preservation of peptidase activity also enables ACE2-Fc to reduce the angiotensin II-mediated cytokine cascade. Furthermore, this Fc domain of ACE2-Fc was shown to activate NK cell degranulation after co-incubation with Spike-expressing H1975 cells. These promising characteristics potentiate the therapeutic prospects of ACE2-Fc as an effective treatment for COVID-19.