Targeting SARS-CoV-2 RNA-dependent RNA polymerase with the coumarin derivative BPR2-D2: Evidence from cell-based and enzymatic studies.
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Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
2025
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| author | Tang, Wen-Fang Tsai, Hui-Ping Chin, Yuan-Fan Tsai, Shan-Ko Lin, Cheng-Chin Ngo, Son Tung Liang, Po-Huang Jheng, Jia-Rong Hsieh, Chung-Fan Lee, Jin-Ching Chang, Yu-Hsiu Chang, Tein-Yao Lin, Chia-Yi Lin, Guan-Hua Cai, Jie-Yun Chen, Yu-Li Chen, Yuan-Siao Liu, Ping-Cheng Yang, Chuen-Mi Shadbahr, Tolou Tang, Jing Wang, Ling-Yu Chen, Cheng Cheung Hsu, Shu-Chen Lee, Hsin-Yi Wang, Wen-Chieh Thai, Quynh Mai Pham, Minh Quan Horng, Jim-Tong |
| author_facet | Tang, Wen-Fang Tsai, Hui-Ping Chin, Yuan-Fan Tsai, Shan-Ko Lin, Cheng-Chin Ngo, Son Tung Liang, Po-Huang Jheng, Jia-Rong Hsieh, Chung-Fan Lee, Jin-Ching Chang, Yu-Hsiu Chang, Tein-Yao Lin, Chia-Yi Lin, Guan-Hua Cai, Jie-Yun Chen, Yu-Li Chen, Yuan-Siao Liu, Ping-Cheng Yang, Chuen-Mi Shadbahr, Tolou Tang, Jing Wang, Ling-Yu Chen, Cheng Cheung Hsu, Shu-Chen Lee, Hsin-Yi Wang, Wen-Chieh Thai, Quynh Mai Pham, Minh Quan Horng, Jim-Tong Tang, Wen-Fang Tsai, Hui-Ping Chin, Yuan-Fan Tsai, Shan-Ko Lin, Cheng-Chin Ngo, Son Tung Liang, Po-Huang Jheng, Jia-Rong Hsieh, Chung-Fan Lee, Jin-Ching Chang, Yu-Hsiu Chang, Tein-Yao Lin, Chia-Yi Lin, Guan-Hua Cai, Jie-Yun Chen, Yu-Li Chen, Yuan-Siao Liu, Ping-Cheng Yang, Chuen-Mi Shadbahr, Tolou Tang, Jing Wang, Ling-Yu Chen, Cheng Cheung Hsu, Shu-Chen Lee, Hsin-Yi Wang, Wen-Chieh Thai, Quynh Mai Pham, Minh Quan Horng, Jim-Tong |
| collection | PubMed - marine biology |
| contents | Targeting SARS-CoV-2 RNA-dependent RNA polymerase with the coumarin derivative BPR2-D2: Evidence from cell-based and enzymatic studies. Tang, Wen-Fang Tsai, Hui-Ping Chin, Yuan-Fan Tsai, Shan-Ko Lin, Cheng-Chin Ngo, Son Tung Liang, Po-Huang Jheng, Jia-Rong Hsieh, Chung-Fan Lee, Jin-Ching Chang, Yu-Hsiu Chang, Tein-Yao Lin, Chia-Yi Lin, Guan-Hua Cai, Jie-Yun Chen, Yu-Li Chen, Yuan-Siao Liu, Ping-Cheng Yang, Chuen-Mi Shadbahr, Tolou Tang, Jing Wang, Ling-Yu Chen, Cheng Cheung Hsu, Shu-Chen Lee, Hsin-Yi Wang, Wen-Chieh Thai, Quynh Mai Pham, Minh Quan Horng, Jim-Tong SARS-CoV-2 Coumarins Antiviral Agents Humans Molecular Docking Simulation Virus Replication COVID-19 Drug Treatment RNA-Dependent RNA Polymerase Chlorocebus aethiops Vero Cells Animals Alanine RNA, Viral Coronavirus RNA-Dependent RNA Polymerase Adenosine Monophosphate COVID-19 The rapid mutation rate of SARS-CoV-2 highlights the urgent need for continuous drug development to enhance both efficacy and safety. BPR2-D2, an angular coumarin derivative, has previously shown notable anti-influenza activity and broad-spectrum inhibitory effects against RNA viruses. In this study, we found that BPR2-D2 exhibits potent antiviral activity against multiple SARS-CoV-2 variants, including several variants of concern, at nanomolar concentrations. Notably, BPR2-D2 effectively disrupted viral RNA and protein synthesis in infected cells while mitigating pro-inflammatory cytokines triggered by viral replication. Our investigation of SARS-CoV-2 RdRp activity employed in silico analyses, including molecular docking, dynamic simulations, and binding free energy calculations. BPR2-D2 demonstrated superior binding affinity to the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 compared to remdesivir. Additionally, it exhibited an increased synergistic inhibitory activity against the viral enzyme when combined with remdesivir. Both cell-based and in vitro enzyme-based RdRp reporter assays validated BPR2-D2's capacity to inhibit SARS-CoV-2 RdRp activity. The potential synergistic interaction between BPR2-D2 and remdesivir was investigated using cell-based combination assays. The results revealed a synergistic effect in reducing SARS-CoV-2 RNA synthesis, consistent with the in silico analysis. Collectively, these findings suggest that BPR2-D2, a repurposed small-molecule compound, effectively inhibits SARS-CoV-2 by modulating its RdRp function. This positions BPR2-D2 as a promising novel antiviral agent, while also providing insights into the complex molecular mechanisms underlying viral replication. |
| format | Artículo científico |
| id | pubmed_40543163 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie |
| record_format | pubmed |
| spellingShingle | Targeting SARS-CoV-2 RNA-dependent RNA polymerase with the coumarin derivative BPR2-D2: Evidence from cell-based and enzymatic studies. Tang, Wen-Fang Tsai, Hui-Ping Chin, Yuan-Fan Tsai, Shan-Ko Lin, Cheng-Chin Ngo, Son Tung Liang, Po-Huang Jheng, Jia-Rong Hsieh, Chung-Fan Lee, Jin-Ching Chang, Yu-Hsiu Chang, Tein-Yao Lin, Chia-Yi Lin, Guan-Hua Cai, Jie-Yun Chen, Yu-Li Chen, Yuan-Siao Liu, Ping-Cheng Yang, Chuen-Mi Shadbahr, Tolou Tang, Jing Wang, Ling-Yu Chen, Cheng Cheung Hsu, Shu-Chen Lee, Hsin-Yi Wang, Wen-Chieh Thai, Quynh Mai Pham, Minh Quan Horng, Jim-Tong SARS-CoV-2 Coumarins Antiviral Agents Humans Molecular Docking Simulation Virus Replication COVID-19 Drug Treatment RNA-Dependent RNA Polymerase Chlorocebus aethiops Vero Cells Animals Alanine RNA, Viral Coronavirus RNA-Dependent RNA Polymerase Adenosine Monophosphate COVID-19 Targeting SARS-CoV-2 RNA-dependent RNA polymerase with the coumarin derivative BPR2-D2: Evidence from cell-based and enzymatic studies. Tang, Wen-Fang Tsai, Hui-Ping Chin, Yuan-Fan Tsai, Shan-Ko Lin, Cheng-Chin Ngo, Son Tung Liang, Po-Huang Jheng, Jia-Rong Hsieh, Chung-Fan Lee, Jin-Ching Chang, Yu-Hsiu Chang, Tein-Yao Lin, Chia-Yi Lin, Guan-Hua Cai, Jie-Yun Chen, Yu-Li Chen, Yuan-Siao Liu, Ping-Cheng Yang, Chuen-Mi Shadbahr, Tolou Tang, Jing Wang, Ling-Yu Chen, Cheng Cheung Hsu, Shu-Chen Lee, Hsin-Yi Wang, Wen-Chieh Thai, Quynh Mai Pham, Minh Quan Horng, Jim-Tong SARS-CoV-2 Coumarins Antiviral Agents Humans Molecular Docking Simulation Virus Replication COVID-19 Drug Treatment RNA-Dependent RNA Polymerase Chlorocebus aethiops Vero Cells Animals Alanine RNA, Viral Coronavirus RNA-Dependent RNA Polymerase Adenosine Monophosphate COVID-19 The rapid mutation rate of SARS-CoV-2 highlights the urgent need for continuous drug development to enhance both efficacy and safety. BPR2-D2, an angular coumarin derivative, has previously shown notable anti-influenza activity and broad-spectrum inhibitory effects against RNA viruses. In this study, we found that BPR2-D2 exhibits potent antiviral activity against multiple SARS-CoV-2 variants, including several variants of concern, at nanomolar concentrations. Notably, BPR2-D2 effectively disrupted viral RNA and protein synthesis in infected cells while mitigating pro-inflammatory cytokines triggered by viral replication. Our investigation of SARS-CoV-2 RdRp activity employed in silico analyses, including molecular docking, dynamic simulations, and binding free energy calculations. BPR2-D2 demonstrated superior binding affinity to the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 compared to remdesivir. Additionally, it exhibited an increased synergistic inhibitory activity against the viral enzyme when combined with remdesivir. Both cell-based and in vitro enzyme-based RdRp reporter assays validated BPR2-D2's capacity to inhibit SARS-CoV-2 RdRp activity. The potential synergistic interaction between BPR2-D2 and remdesivir was investigated using cell-based combination assays. The results revealed a synergistic effect in reducing SARS-CoV-2 RNA synthesis, consistent with the in silico analysis. Collectively, these findings suggest that BPR2-D2, a repurposed small-molecule compound, effectively inhibits SARS-CoV-2 by modulating its RdRp function. This positions BPR2-D2 as a promising novel antiviral agent, while also providing insights into the complex molecular mechanisms underlying viral replication. |
| title | Targeting SARS-CoV-2 RNA-dependent RNA polymerase with the coumarin derivative BPR2-D2: Evidence from cell-based and enzymatic studies. |
| topic | SARS-CoV-2 Coumarins Antiviral Agents Humans Molecular Docking Simulation Virus Replication COVID-19 Drug Treatment RNA-Dependent RNA Polymerase Chlorocebus aethiops Vero Cells Animals Alanine RNA, Viral Coronavirus RNA-Dependent RNA Polymerase Adenosine Monophosphate COVID-19 |
| url | https://pubmed.ncbi.nlm.nih.gov/40543163/ |