Location
Suwanee, GA
Start Date
7-5-2024 1:00 PM
End Date
7-5-2024 4:00 PM
Description
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, remains a substantial global public health threat. Despite widespread vaccination efforts, reinfection rates are rising, necessitating a comprehensive examination of vaccine effectiveness against emerging variants. There is an immediate and pressing need to identify potential therapeutic interventions for combating resistant COVID-19 infections. Research has highlighted the significance of nonstructural proteins, including proteases and polymerases, in viral replication, making them attractive targets for drug development. Among these, the Papain-like protease (PLpro), 3-chymotrypsin-like protease (3CLpro), and RNA-dependent RNA polymerase (RdRp) enzymes play pivotal roles in SARS-CoV-2 replication and are promising candidates for drug targeting. Currently, two antiviral drugs, LagevrioTM (an RdRp inhibitor) and Paxlovid® (a 3CLPro inhibitor), are available for COVID-19 treatment. However, the market lacks drugs targeting the PLP enzyme, which is essential for viral replication and suppression of the host's antiviral immune response. Additionally, SARS-CoV-2 PLpro exhibits deubiquitination (DUB) activity. The DUB activity of SARS-CoV-2 PLpro disrupts the host's antiviral immune response. Hence, our objective is to assess derivatives from Salvia miltiorrhiza against the SARS-CoV-2 PLpro enzyme, evaluating both its proteolytic and DUB activities. In this study, we tested twenty-one derivatives from Salvia miltiorrhiza against the PLpro enzyme, and among them, 19 were found to inhibit more than 50% of the proteolytic activity of SARS-CoV-2 PLpro at a concentration of 50uM. Furthermore, dose-response experiments revealed that the IC50 values of these 19 derivatives against PLpro proteolytic activity ranged from 0.25 to 31.02uM. We are actively investigating the inhibition of Salvia miltiorrhiza derivatives against DUB activity of PLpro. Additionally, we will evaluate the inhibition kinetics of these compounds against both proteolytic and DUB activities of PLpro, along with conducting in vitro cytotoxicity assessments. Our data suggest that the Salvia miltiorrhiza derivatives inhibit the SARS-CoV-2 viral replicative activity of the PLpro enzyme. However, pre-clinical studies need to validate the therapeutic potential and safety of these antibiotics before being considered for clinical trials.
Embargo Period
7-8-2024
Included in
Inhibition of SARS-CoV-2 papain-like protease by bioactive compounds found in Salvia miltiorrhiza
Suwanee, GA
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, remains a substantial global public health threat. Despite widespread vaccination efforts, reinfection rates are rising, necessitating a comprehensive examination of vaccine effectiveness against emerging variants. There is an immediate and pressing need to identify potential therapeutic interventions for combating resistant COVID-19 infections. Research has highlighted the significance of nonstructural proteins, including proteases and polymerases, in viral replication, making them attractive targets for drug development. Among these, the Papain-like protease (PLpro), 3-chymotrypsin-like protease (3CLpro), and RNA-dependent RNA polymerase (RdRp) enzymes play pivotal roles in SARS-CoV-2 replication and are promising candidates for drug targeting. Currently, two antiviral drugs, LagevrioTM (an RdRp inhibitor) and Paxlovid® (a 3CLPro inhibitor), are available for COVID-19 treatment. However, the market lacks drugs targeting the PLP enzyme, which is essential for viral replication and suppression of the host's antiviral immune response. Additionally, SARS-CoV-2 PLpro exhibits deubiquitination (DUB) activity. The DUB activity of SARS-CoV-2 PLpro disrupts the host's antiviral immune response. Hence, our objective is to assess derivatives from Salvia miltiorrhiza against the SARS-CoV-2 PLpro enzyme, evaluating both its proteolytic and DUB activities. In this study, we tested twenty-one derivatives from Salvia miltiorrhiza against the PLpro enzyme, and among them, 19 were found to inhibit more than 50% of the proteolytic activity of SARS-CoV-2 PLpro at a concentration of 50uM. Furthermore, dose-response experiments revealed that the IC50 values of these 19 derivatives against PLpro proteolytic activity ranged from 0.25 to 31.02uM. We are actively investigating the inhibition of Salvia miltiorrhiza derivatives against DUB activity of PLpro. Additionally, we will evaluate the inhibition kinetics of these compounds against both proteolytic and DUB activities of PLpro, along with conducting in vitro cytotoxicity assessments. Our data suggest that the Salvia miltiorrhiza derivatives inhibit the SARS-CoV-2 viral replicative activity of the PLpro enzyme. However, pre-clinical studies need to validate the therapeutic potential and safety of these antibiotics before being considered for clinical trials.