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
- Antimicrob Agents Chemother. 2024 Apr 3;68(4):e0095623. doi: 10.1128/aac.00956-23.
- 1. Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan.
- 2. Institute of Preventive Medicine, National Defense Medical Center, New Taipei, Taiwan.
- 3. Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan.
- 4. Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
- 5. Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan.
- 6. Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
- 7. Department of Pathology and Graduate Institute of Pathology and Parasitology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
- 8. Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan.
- 9. Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
- 10. Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
- 11. Research Center for Industry of Human Ecology and Research Center for Chinese Herbal Medicine, Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
- 12. Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.
- 13. Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan.
- 14. Division of Medical Oncology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
- 15. Institute of Biotechnology and Pharmaceutical Research, Value-Added MedChem Innovation Center, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
- 16. Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
- # Contributed equally.
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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Cat. No.Product NameDescriptionTargetResearch Area
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Research Areas: Infection