2. Academic Validation
  3. 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

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.
Wen-Fang Tang # 1,  Yu-Hsiu Chang # 2 3,  Cheng-Chin Lin # 4,  Jia-Rong Jheng # 5,  Chung-Fan Hsieh # 1 6,  Yuan-Fan Chin # 3,  Tein-Yao Chang # 2 7,  Jin-Ching Lee # 8 9,  Po-Huang Liang # 10,  Chia-Yi Lin 1,  Guan-Hua Lin 1,  Jie-Yun Cai 1,  Yu-Li Chen 11,  Yuan-Siao Chen 5,  Shan-Ko Tsai 2,  Ping-Cheng Liu 2,  Chuen-Mi Yang 2,  Tolou Shadbahr 12,  Jing Tang 12,  Yu-Lin Hsu 2,  Chih-Heng Huang 2 3 13,  Ling-Yu Wang 5 14,  Cheng Cheung Chen 2 13,  Jyh-Hwa Kau 2 13,  Yi-Jen Hung 2,  Hsin-Yi Lee 15,  Wen-Chieh Wang 15,  Hui-Ping Tsai 2,  Jim-Tong Horng 1 5 11 16
Affiliations

Affiliations

  • 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.
PMID: 38446062 DOI: 10.1128/aac.00956-23
Abstract

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.

Keywords

BPR3P0128; RdRp reporter assay; SARS-CoV-2; antiviral; broad-spectrum antiviral; remdesivir; synergistic effect.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-161356
    RNA-dependent RNA Polymerase Inhibitor