tetano
Editor, Senior Moderator
Biomed Pharmacother
. 2025 Jun 20:189:118252.
doi: 10.1016/j.biopha.2025.118252. Online ahead of print. Targeting SARS-CoV-2 RNA-dependent RNA polymerase with the coumarin derivative BPR2-D2: Evidence from cell-based and enzymatic studies
Wen-Fang Tang[SUP] 1 [/SUP], Hui-Ping Tsai[SUP] 2 [/SUP], Yuan-Fan Chin[SUP] 2 [/SUP], Shan-Ko Tsai[SUP] 3 [/SUP], Cheng-Chin Lin[SUP] 4 [/SUP], Son Tung Ngo[SUP] 5 [/SUP], Po-Huang Liang[SUP] 6 [/SUP], Jia-Rong Jheng[SUP] 7 [/SUP], Chung-Fan Hsieh[SUP] 8 [/SUP], Jin-Ching Lee[SUP] 9 [/SUP], Yu-Hsiu Chang[SUP] 10 [/SUP], Tein-Yao Chang[SUP] 11 [/SUP], Chia-Yi Lin[SUP] 1 [/SUP], Guan-Hua Lin[SUP] 1 [/SUP], Jie-Yun Cai[SUP] 1 [/SUP], Yu-Li Chen[SUP] 12 [/SUP], Yuan-Siao Chen[SUP] 7 [/SUP], Ping-Cheng Liu[SUP] 2 [/SUP], Chuen-Mi Yang[SUP] 2 [/SUP], Tolou Shadbahr[SUP] 13 [/SUP], Jing Tang[SUP] 13 [/SUP], Ling-Yu Wang[SUP] 14 [/SUP], Cheng Cheung Chen[SUP] 3 [/SUP], Shu-Chen Hsu[SUP] 3 [/SUP], Hsin-Yi Lee[SUP] 15 [/SUP], Wen-Chieh Wang[SUP] 15 [/SUP], Quynh Mai Thai[SUP] 5 [/SUP], Minh Quan Pham[SUP] 16 [/SUP], Jim-Tong Horng[SUP] 17 [/SUP]
Affiliations
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.
Keywords: Antiviral; BPR2-D2; Non-nucleoside inhibitor; RdRp inhibitor; Severe acute respiratory syndrome coronavirus 2; Synergistic effect.
. 2025 Jun 20:189:118252.
doi: 10.1016/j.biopha.2025.118252. Online ahead of print. Targeting SARS-CoV-2 RNA-dependent RNA polymerase with the coumarin derivative BPR2-D2: Evidence from cell-based and enzymatic studies
Wen-Fang Tang[SUP] 1 [/SUP], Hui-Ping Tsai[SUP] 2 [/SUP], Yuan-Fan Chin[SUP] 2 [/SUP], Shan-Ko Tsai[SUP] 3 [/SUP], Cheng-Chin Lin[SUP] 4 [/SUP], Son Tung Ngo[SUP] 5 [/SUP], Po-Huang Liang[SUP] 6 [/SUP], Jia-Rong Jheng[SUP] 7 [/SUP], Chung-Fan Hsieh[SUP] 8 [/SUP], Jin-Ching Lee[SUP] 9 [/SUP], Yu-Hsiu Chang[SUP] 10 [/SUP], Tein-Yao Chang[SUP] 11 [/SUP], Chia-Yi Lin[SUP] 1 [/SUP], Guan-Hua Lin[SUP] 1 [/SUP], Jie-Yun Cai[SUP] 1 [/SUP], Yu-Li Chen[SUP] 12 [/SUP], Yuan-Siao Chen[SUP] 7 [/SUP], Ping-Cheng Liu[SUP] 2 [/SUP], Chuen-Mi Yang[SUP] 2 [/SUP], Tolou Shadbahr[SUP] 13 [/SUP], Jing Tang[SUP] 13 [/SUP], Ling-Yu Wang[SUP] 14 [/SUP], Cheng Cheung Chen[SUP] 3 [/SUP], Shu-Chen Hsu[SUP] 3 [/SUP], Hsin-Yi Lee[SUP] 15 [/SUP], Wen-Chieh Wang[SUP] 15 [/SUP], Quynh Mai Thai[SUP] 5 [/SUP], Minh Quan Pham[SUP] 16 [/SUP], Jim-Tong Horng[SUP] 17 [/SUP]
Affiliations
- PMID: 40543163
- DOI: 10.1016/j.biopha.2025.118252
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.
Keywords: Antiviral; BPR2-D2; Non-nucleoside inhibitor; RdRp inhibitor; Severe acute respiratory syndrome coronavirus 2; Synergistic effect.