1. Assessing the inhibitory effects of some secondary amines, thioureas and 1,3-dimethyluracil conjugates of (-)-cytisine and thermopsine on the RNA-dependent RNA polymerase of SARS-CoV-1 and SARS-CoV-2.
- Author
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Chen Y, Hour MJ, Lin CS, Chang YS, Chen ZY, Koval'skaya AV, Su WC, Tsypysheva IP, and Lin CW
- Subjects
- Humans, Azocines pharmacology, Azocines chemistry, Azocines chemical synthesis, Coronavirus RNA-Dependent RNA Polymerase antagonists & inhibitors, Coronavirus RNA-Dependent RNA Polymerase metabolism, Cytidine analogs & derivatives, Cytidine pharmacology, Cytidine chemistry, Cytidine chemical synthesis, Severe acute respiratory syndrome-related coronavirus drug effects, Severe acute respiratory syndrome-related coronavirus enzymology, Structure-Activity Relationship, Uracil analogs & derivatives, Uracil pharmacology, Uracil chemistry, Uracil chemical synthesis, Antiviral Agents pharmacology, Antiviral Agents chemistry, Antiviral Agents chemical synthesis, Quinolizines pharmacology, Quinolizines chemistry, Quinolizines chemical synthesis, RNA-Dependent RNA Polymerase antagonists & inhibitors, RNA-Dependent RNA Polymerase metabolism, SARS-CoV-2 drug effects, SARS-CoV-2 enzymology
- Abstract
SARS-CoV-2 causes COVID-19, with symptoms ranging from mild to severe, including pneumonia and death. This beta coronavirus has a 30-kilobase RNA genome and shares about 80 % of its nucleotide sequence with SARS-CoV-1. The replication/transcription complex, essential for viral RNA synthesis, includes RNA-dependent RNA polymerase (RdRp, nsp12) enhanced by nsp7 and nsp8. Antivirals like molnupiravir and remdesivir, which are RdRp inhibitors, treat severe COVID-19 but have limitations, highlighting the need for new therapies. This study assessed (-)-cytisine, methylcytisine, and thermopsine derivatives against SARS-CoV-1 and SARS-CoV-2 in vitro, focusing on their RdRp inhibition. Selected compounds from a previous study were evaluated using a SARS-CoV-2 RNA polymerase assay kit to investigate their structure-activity relationships. Compound 17 (1,3-dimethyluracil conjugate with (-)-cytisine and thermopsine) emerged as a potent inhibitor of SARS-CoV-1 and SARS-CoV-2 RdRp, with an IC50 value of 7.8 μM against SARS-CoV-2 RdRp. It showed a dose-dependent reduction in cytopathic effects in cells infected with SARS-CoV-1 and SARS-CoV-2 replicon-based single-round infectious particles (SRIPs) and significantly inhibited SARS-CoV N protein expression, with EC50 values of 0.12 µM for SARS-CoV-1 and 1.47 µM for SARS-CoV-2 SRIPs. Additionally, compound 17 reduced viral subgenomic RNA levels in a concentration-dependent manner in SRIP-infected cells. The structure-activity relationships of compound 17 with SARS-CoV-1 and SARS-CoV-2 RdRp were also investigated, highlighting it as a promising lead for developing antiviral agents against SARS and COVID-19., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.) more...
- Published
- 2024
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