BPR3P0128, a non-nucleoside RNA-dependent RNA polymerase inhibitor, inhibits SARS-CoV-2 variants of concern and exerts synergistic antiviral activity in combination with remdesivir
Viral RNA-dependent RNA polymerase (RdRp), a highly conserved molecule in RNA viruses, has recently emerged as a promising drug target for broad-acting inhibitors. Through a Vero E6-based anti-cytopathic effect assay, we found that BPR3P0128, which incorporates a quinoline core similar to hydroxychloroquine, outperformed the adenosine analog remdesivir in inhibiting RdRp activity (EC50 = 0.66 µM and 3 µM, respectively). BPR3P0128 demonstrated broad-spectrum activity against various severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. When introduced after viral adsorption, BPR3P0128 significantly decreased SARS-CoV-2 replication; however, it did not affect the early entry stage, as evidenced by a time-of-drug-addition assay. This suggests that BPR3P0128's primary action takes place during viral replication. We also found that BPR3P0128 effectively reduced the expression of proinflammatory cytokines in human lung epithelial Calu-3 cells infected with SARS-CoV-2. Molecular docking analysis showed that BPR3P0128 targets the RdRp channel, inhibiting substrate entry, which implies it operates differently-but complementary-with remdesivir. Utilizing an optimized cell-based minigenome RdRp reporter assay, we confirmed that BPR3P0128 exhibited potent inhibitory activity. However, an enzyme-based RdRp assay employing purified recombinant nsp12/nsp7/nsp8 failed to corroborate this inhibitory activity. This suggests that BPR3P0128 may inhibit activity by targeting host-related RdRp-associated factors. Moreover, we discovered that a combination of BPR3P0128 and remdesivir had a synergistic effect-a result likely due to both drugs interacting with separate domains of the RdRp. This novel synergy between the two drugs reinforces the potential clinical value of the BPR3P0128-remdesivir combination in combating various SARS-CoV-2 variants of concern.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:68 |
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| Enthalten in: |
Antimicrobial agents and chemotherapy - 68(2024), 4 vom: 03. Apr., Seite e0095623 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tang, Wen-Fang [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 04.04.2024 Date Revised 05.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1128/aac.00956-23 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369358945 |
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| 245 | 1 | 0 | |a BPR3P0128, a non-nucleoside RNA-dependent RNA polymerase inhibitor, inhibits SARS-CoV-2 variants of concern and exerts synergistic antiviral activity in combination with remdesivir |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Viral RNA-dependent RNA polymerase (RdRp), a highly conserved molecule in RNA viruses, has recently emerged as a promising drug target for broad-acting inhibitors. Through a Vero E6-based anti-cytopathic effect assay, we found that BPR3P0128, which incorporates a quinoline core similar to hydroxychloroquine, outperformed the adenosine analog remdesivir in inhibiting RdRp activity (EC50 = 0.66 µM and 3 µM, respectively). BPR3P0128 demonstrated broad-spectrum activity against various severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. When introduced after viral adsorption, BPR3P0128 significantly decreased SARS-CoV-2 replication; however, it did not affect the early entry stage, as evidenced by a time-of-drug-addition assay. This suggests that BPR3P0128's primary action takes place during viral replication. We also found that BPR3P0128 effectively reduced the expression of proinflammatory cytokines in human lung epithelial Calu-3 cells infected with SARS-CoV-2. Molecular docking analysis showed that BPR3P0128 targets the RdRp channel, inhibiting substrate entry, which implies it operates differently-but complementary-with remdesivir. Utilizing an optimized cell-based minigenome RdRp reporter assay, we confirmed that BPR3P0128 exhibited potent inhibitory activity. However, an enzyme-based RdRp assay employing purified recombinant nsp12/nsp7/nsp8 failed to corroborate this inhibitory activity. This suggests that BPR3P0128 may inhibit activity by targeting host-related RdRp-associated factors. Moreover, we discovered that a combination of BPR3P0128 and remdesivir had a synergistic effect-a result likely due to both drugs interacting with separate domains of the RdRp. This novel synergy between the two drugs reinforces the potential clinical value of the BPR3P0128-remdesivir combination in combating various SARS-CoV-2 variants of concern | ||
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| 700 | 1 | |a Hsieh, Chung-Fan |e verfasserin |4 aut | |
| 700 | 1 | |a Chin, Yuan-Fan |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Tein-Yao |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Jin-Ching |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Po-Huang |e verfasserin |4 aut | |
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| 700 | 1 | |a Chen, Yu-Li |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yuan-Siao |e verfasserin |4 aut | |
| 700 | 1 | |a Tsai, Shan-Ko |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Ping-Cheng |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Chuen-Mi |e verfasserin |4 aut | |
| 700 | 1 | |a Shadbahr, Tolou |e verfasserin |4 aut | |
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| 700 | 1 | |a Kau, Jyh-Hwa |e verfasserin |4 aut | |
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| 700 | 1 | |a Tsai, Hui-Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Horng, Jim-Tong |e verfasserin |4 aut | |
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