Sofalcone

A review.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isthe causative viral pathogen of the coronavirus disease 2019 (COVID-19), which has led to 250 million infections and more than 5.00 million deaths worldwide by the middle of Oct., 2021(WHO).Thus, SARS-CoV-2 RNA repair complex inhibitor sofalcone and senolytics could beapplied to treat COVID-19 infections.Furthermore, oral administration of these senolytics to animal model of COVID-19 infections reduced systemic inflammation and mitigated the diseases.

The risk of zoonotic coronavirus spillover into the human population, as highlighted by the SARS-CoV-2 pandemic, demands the development of pan-coronavirus antivirals. The efficacy of existing antiviral ribonucleoside/ribonucleotide analogs, such as remdesivir, is decreased by the viral proofreading exonuclease NSP14-NSP10 complex. Here, using a novel assay and in silico modeling and screening, we identified NSP14-NSP10 inhibitors that increase remdesivir’s potency. A model compound, sofalcone, both inhibits the exonuclease activity of SARS-CoV-2, SARS-CoV, and MERS-CoV in vitro, and synergistically enhances the antiviral effect of remdesivir, suppressing the replication of SARS-CoV-2 and the related human coronavirus OC43. The validation of top hits from our primary screenings using cellular systems provides proof-of-concept for the NSP14 complex as a therapeutic target.