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

Article

Author: Lin, Cheng-Chin ; Chin, Yuan-Fan ; Cai, Jie-Yun ; Lin, Guan-Hua ; Huang, Chih-Heng ; Liu, Ping-Cheng ; Tang, Jing ; Kau, Jyh-Hwa ; Jheng, Jia-Rong ; Hung, Yi-Jen ; Chang, Tein-Yao ; Tsai, Hui-Ping ; Chen, Yuan-Siao ; Horng, Jim-Tong ; Lee, Jin-Ching ; Chen, Cheng Cheung ; Lin, Chia-Yi ; Liang, Po-Huang ; Tsai, Shan-Ko ; Yang, Chuen-Mi ; Lee, Hsin-Yi ; Wang, Ling-Yu ; Hsieh, Chung-Fan ; Wang, Wen-Chieh ; Chen, Yu-Li ; Chang, Yu-Hsiu ; Shadbahr, Tolou ; Hsu, Yu-Lin ; Tang, Wen-Fang

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 (EC 50 = 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.

01 Aug 2021·Journal of Infection

Remdesivir treatment and transient bradycardia in patients with coronavirus diseases 2019 (COVID-19)

Letter

Author: Suardi, Lorenzo Roberto ; Francisci, Daniela ; Pallotto, Carlo ; Salomoni, Elena ; Gabbuti, Andrea ; Pietro, Massimo Antonio Di ; Attala, Letizia ; Vichi, Francesca ; Mecocci, Lorenzo ; Blanc, Pierluigi ; Baragli, Filippo ; Pierotti, Piera ; Esposti, Anna Degli ; Esperti, Sara

Remdesivir, a viral RNA-dependent RNA-polymerase inhibitor, was authorized for severe COVID-19 patients without mech. ventilation 4 but still little is known about its safety except for reports about hepatic disorders and skin reactions.More recently, concern arose about RDV-related cardiac adverse events, especially bradycardia.The purpose of this study is to describe bradycardia incidence in a group of directly-observed COVID-19 patients and its possible association with RDV.

01 Jun 2021·PhytomedicineQ2 · MEDICINE

Lycorine, a non-nucleoside RNA dependent RNA polymerase inhibitor, as potential treatment for emerging coronavirus infections

Q2 · MEDICINE

Article

Author: Song, Jong Hwan ; Park, Tamina ; Kwon, Sunoh ; Jang, Min Seong ; Jin, Young-Hee ; Jeon, Sangeun ; Min, Jung Sun ; Lee, Jihye ; Kim, Hyoung Rae ; Kim, Seungtaek ; Park, Chul Min ; Park, Daeui

BACKGROUNDHighly effective novel treatments need to be developed to suppress emerging coronavirus (CoV) infections such as COVID-19. The RNA dependent RNA polymerase (RdRp) among the viral proteins is known as an effective antiviral target. Lycorine is a phenanthridine Amaryllidaceae alkaloid isolated from the bulbs of Lycoris radiata (L'Hér.) Herb. and has various pharmacological bioactivities including antiviral function.PURPOSEWe investigated the direct-inhibiting action of lycorine on CoV's RdRp, as potential treatment for emerging CoV infections.METHODSWe examined the inhibitory effect of lycorine on MERS-CoV, SARS-CoV, and SARS-CoV-2 infections, and then quantitatively measured the inhibitory effect of lycorine on MERS-CoV RdRp activity using a cell-based reporter assay. Finally, we performed the docking simulation with lycorine and SARS-CoV-2 RdRp.RESULTSLycorine efficiently inhibited these CoVs with IC₅₀ values of 2.123 ± 0.053, 1.021 ± 0.025, and 0.878 ± 0.022 μM, respectively, comparable with anti-CoV effects of remdesivir. Lycorine directly inhibited MERS-CoV RdRp activity with an IC₅₀ of 1.406 ± 0.260 μM, compared with remdesivir's IC₅₀ value of 6.335 ± 0.731 μM. In addition, docking simulation showed that lycorine interacts with SARS-CoV-2 RdRp at the Asp623, Asn691, and Ser759 residues through hydrogen bonding, at which the binding affinities of lycorine (-6.2 kcal/mol) were higher than those of remdesivir (-4.7 kcal/mol).CONCLUSIONSLycorine is a potent non-nucleoside direct-acting antiviral against emerging coronavirus infections and acts by inhibiting viral RdRp activity; therefore, lycorine may be a candidate against the current COVID-19 pandemic.

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Indication	Highest Phase	Country/Location	Organization	Date
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