RESUMO
The twenty-first century has already recorded more than ten major epidemics or pandemics of viral disease, including the devastating COVID-19. Novel effective antivirals with broad-spectrum coverage are urgently needed. Herein, we reported a novel broad-spectrum antiviral compound PAC5. Oral administration of PAC5 eliminated HBV cccDNA and reduced the large antigen load in distinct mouse models of HBV infection. Strikingly, oral administration of PAC5 in a hamster model of SARS-CoV-2 omicron (BA.1) infection significantly decreases viral loads and attenuates lung inflammation. Mechanistically, PAC5 binds to a pocket near Asp49 in the RNA recognition motif of hnRNPA2B1. PAC5-bound hnRNPA2B1 is extensively activated and translocated to the cytoplasm where it initiates the TBK1-IRF3 pathway, leading to the production of type I IFNs with antiviral activity. Our results indicate that PAC5 is a novel small-molecule agonist of hnRNPA2B1, which may have a role in dealing with emerging infectious diseases now and in the future.
Assuntos
Animais , Camundongos , Antivirais/farmacologia , COVID-19 , Vírus da Hepatite B , Interferon Tipo I/metabolismo , SARS-CoV-2/efeitos dos fármacos , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/antagonistas & inibidoresRESUMO
Traditional Chinese Medicine (TCM) is an important reservoir for bioactive natural products. TCM extraction methods by water decoction and wine tincture are an integral part of TCM and essential for their widely acknowledged efficacy. In this study, we selected 6 common TCMs that are rich in chemistry to investigate whether the TCM extraction methods deliver molecules with drug-like physical chemical properties. Six TCM herbal materials were extracted by water, 95% ethanol, and sequential hexane, dichloromethane and methanol. The extracts were analyzed by HPLC and H NMR. Isolation on one of the extracts yielded 32 compounds, their physical chemical properties were analyzed by Instant JChem. Our results showed that ethanol extraction, which mimics TCM wine tincture, delivered compounds with physical chemical properties compliant to Lipinski's rule of 5.