tetano
Editor, Senior Moderator
Antimicrob Agents Chemother
. 2024 Mar 6:e0095623.
doi: 10.1128/aac.00956-23. Online ahead of print. 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
Wen-Fang Tang[SUP] #[/SUP][SUP] 1 [/SUP], Yu-Hsiu Chang[SUP] #[/SUP][SUP] 2 3 [/SUP], Cheng-Chin Lin[SUP] #[/SUP][SUP] 4 [/SUP], Jia-Rong Jheng[SUP] #[/SUP][SUP] 5 [/SUP], Chung-Fan Hsieh[SUP] #[/SUP][SUP] 1 6 [/SUP], Yuan-Fan Chin[SUP] #[/SUP][SUP] 3 [/SUP], Tein-Yao Chang[SUP] #[/SUP][SUP] 2 7 [/SUP], Jin-Ching Lee[SUP] #[/SUP][SUP] 8 9 [/SUP], Po-Huang Liang[SUP] #[/SUP][SUP] 10 [/SUP], Chia-Yi Lin[SUP] 1 [/SUP], Guan-Hua Lin[SUP] 1 [/SUP], Jie-Yun Cai[SUP] 1 [/SUP], Yu-Li Chen[SUP] 11 [/SUP], Yuan-Siao Chen[SUP] 5 [/SUP], Shan-Ko Tsai[SUP] 2 [/SUP], Ping-Cheng Liu[SUP] 2 [/SUP], Chuen-Mi Yang[SUP] 2 [/SUP], Tolou Shadbahr[SUP] 12 [/SUP], Jing Tang[SUP] 12 [/SUP], Yu-Lin Hsu[SUP] 2 [/SUP], Chih-Heng Huang[SUP] 2 3 13 [/SUP], Ling-Yu Wang[SUP] 5 14 [/SUP], Cheng Cheung Chen[SUP] 2 13 [/SUP], Jyh-Hwa Kau[SUP] 2 13 [/SUP], Yi-Jen Hung[SUP] 2 [/SUP], Hsin-Yi Lee[SUP] 15 [/SUP], Wen-Chieh Wang[SUP] 15 [/SUP], Hui-Ping Tsai[SUP] 2 [/SUP], Jim-Tong Horng[SUP] 1 5 11 16 [/SUP]
Affiliations
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 (EC[SUB]50[/SUB] = 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.
Keywords: BPR3P0128; RdRp reporter assay; SARS-CoV-2; antiviral; broad-spectrum antiviral; remdesivir; synergistic effect.
. 2024 Mar 6:e0095623.
doi: 10.1128/aac.00956-23. Online ahead of print. 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
Wen-Fang Tang[SUP] #[/SUP][SUP] 1 [/SUP], Yu-Hsiu Chang[SUP] #[/SUP][SUP] 2 3 [/SUP], Cheng-Chin Lin[SUP] #[/SUP][SUP] 4 [/SUP], Jia-Rong Jheng[SUP] #[/SUP][SUP] 5 [/SUP], Chung-Fan Hsieh[SUP] #[/SUP][SUP] 1 6 [/SUP], Yuan-Fan Chin[SUP] #[/SUP][SUP] 3 [/SUP], Tein-Yao Chang[SUP] #[/SUP][SUP] 2 7 [/SUP], Jin-Ching Lee[SUP] #[/SUP][SUP] 8 9 [/SUP], Po-Huang Liang[SUP] #[/SUP][SUP] 10 [/SUP], Chia-Yi Lin[SUP] 1 [/SUP], Guan-Hua Lin[SUP] 1 [/SUP], Jie-Yun Cai[SUP] 1 [/SUP], Yu-Li Chen[SUP] 11 [/SUP], Yuan-Siao Chen[SUP] 5 [/SUP], Shan-Ko Tsai[SUP] 2 [/SUP], Ping-Cheng Liu[SUP] 2 [/SUP], Chuen-Mi Yang[SUP] 2 [/SUP], Tolou Shadbahr[SUP] 12 [/SUP], Jing Tang[SUP] 12 [/SUP], Yu-Lin Hsu[SUP] 2 [/SUP], Chih-Heng Huang[SUP] 2 3 13 [/SUP], Ling-Yu Wang[SUP] 5 14 [/SUP], Cheng Cheung Chen[SUP] 2 13 [/SUP], Jyh-Hwa Kau[SUP] 2 13 [/SUP], Yi-Jen Hung[SUP] 2 [/SUP], Hsin-Yi Lee[SUP] 15 [/SUP], Wen-Chieh Wang[SUP] 15 [/SUP], Hui-Ping Tsai[SUP] 2 [/SUP], Jim-Tong Horng[SUP] 1 5 11 16 [/SUP]
Affiliations
- PMID: 38446062
- DOI: 10.1128/aac.00956-23
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 (EC[SUB]50[/SUB] = 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.
Keywords: BPR3P0128; RdRp reporter assay; SARS-CoV-2; antiviral; broad-spectrum antiviral; remdesivir; synergistic effect.