Remdesivir inhibits the polymerases of the novel filoviruses Lloviu and Bombali virus

Bodmer, Bianca S.; Zierke, Lukas; Wendt, Lisa; Greßler, Josephin; Groseth, Allison; Hoenen, Thomas

doi:10.1016/j.antiviral.2021.105120

Cited by 12 publications

(2 citation statements)

References 39 publications

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“…nucleoside analog known to inhibit EBOV RNA synthesis [24], confirming recently published results using a LLOV minigenome system [25]. Parallel analysis using U18666A, an inhibitor of the filovirus receptor Niemann-Pick C1 (NPC1) previously shown to inhibit EBOV entry [26,27], also showed inhibition of both viruses in both cell types (Figs 5B and S8), which is in line with previous results indicating that LLOV uses NPC1 to mediate cell entry [28].…”

Section: Plos Pathogenssupporting

confidence: 90%

Recombinant Lloviu virus as a tool to study viral replication and host responses

et al. 2022

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Next generation sequencing has revealed the presence of numerous RNA viruses in animal reservoir hosts, including many closely related to known human pathogens. Despite their zoonotic potential, most of these viruses remain understudied due to not yet being cultured. While reverse genetic systems can facilitate virus rescue, this is often hindered by missing viral genome ends. A prime example is Lloviu virus (LLOV), an uncultured filovirus that is closely related to the highly pathogenic Ebola virus. Using minigenome systems, we complemented the missing LLOV genomic ends and identified cis-acting elements required for LLOV replication that were lacking in the published sequence. We leveraged these data to generate recombinant full-length LLOV clones and rescue infectious virus. Similar to other filoviruses, recombinant LLOV (rLLOV) forms filamentous virions and induces the formation of characteristic inclusions in the cytoplasm of the infected cells, as shown by electron microscopy. Known target cells of Ebola virus, including macrophages and hepatocytes, are permissive to rLLOV infection, suggesting that humans could be potential hosts. However, inflammatory responses in human macrophages, a hallmark of Ebola virus disease, are not induced by rLLOV. Additional tropism testing identified pneumocytes as capable of robust rLLOV and Ebola virus infection. We also used rLLOV to test antivirals targeting multiple facets of the replication cycle. Rescue of uncultured viruses of pathogenic concern represents a valuable tool in our arsenal for pandemic preparedness.

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Section: Plos Pathogenssupporting

confidence: 90%

Recombinant Lloviu virus as a tool to study viral replication and host responses

et al. 2022

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“…Comparing rLLOVcomp and rEBOV in both human and bat cells, we found similar inhibition of each virus in both cell types by remdesivir (Fig. 3d), a nucleoside analog known to inhibit EBOV RNA synthesis 24 , confirming recently published results using a LLOV minigenome system 25 . Parallel analysis using U18666A, an inhibitor of the filovirus receptor Niemann-Pick C1 (NPC1) previously shown to inhibit EBOV entry 26,27 , also showed inhibition of both viruses in both cell types (Fig.…”

Section: Use Of Rllovcomp To Test the Efficacy Of Potential Therapeuticssupporting

confidence: 89%

Recombinant Lloviu virus as a model to study inaccessible zoonotic viruses

Hume

Heiden

Olejnik

et al. 2021

Preprint

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Next generation sequencing has revealed the presence of many RNA viruses in animal reservoir hosts, including many closely related to known human pathogens. Despite their zoonotic potential, many of these viruses remain understudied due to not yet being cultured. While reverse genetic systems can facilitate virus rescue, this is often hindered by missing viral genome ends. A prime example is Lloviu virus (LLOV), an uncultured filovirus that is closely related to the highly pathogenic Ebola virus. Using minigenome systems, we complemented the missing LLOV genomic ends and identified cis-acting elements required for LLOV replication that were lacking in the published sequence. We leveraged these data to generate recombinant full-length LLOV clones and rescue infectious virus. Recombinant LLOV (rLLOV) displays typical filovirus features, as shown by electron microscopy. Known target cells of Ebola virus, including macrophages and hepatocytes, are permissive to rLLOV infection, suggesting that humans could be potential hosts. However, inflammatory responses in human macrophages, a hallmark of Ebola virus disease, are not induced by rLLOV. We also used rLLOV to test antivirals targeting multiple facets of the replication cycle. Rescue of uncultured viruses of pathogenic concern represents a valuable tool in our arsenal against pandemic preparedness.

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Design of novel broad‐spectrum antiviral nucleoside analogues using natural bases ring‐opening strategy

Du,

Yang,

Zhao

et al. 2024

Drug Development Research

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The global prevalence of RNA virus infections has presented significant challenges to public health in recent years, necessitating the expansion of its alternative therapeutic library. Due to its evolutional conservation, RNA‐dependent RNA polymerase (RdRp) has emerged as a potential target for broad‐spectrum antiviral nucleoside analogues. However, after over half a century of structural modification, exploring unclaimed chemical space using frequently‐used structural substitution methods to design new nucleoside analogues is challenging. In this study, we explore the use of the “ring‐opening” strategy to design new base mimics, thereby using these base mimics to design new nucleoside analogues with broad‐spectrum antiviral activities. A total of 29 compounds were synthesized. Their activity against viral RdRp was initially screened using an influenza A virus RdRp high‐throughput screening model. Then, the antiviral activity of 38a was verified against influenza virus strain A/PR/8/34 (H1N1), demonstrating a 50% inhibitory concentration (IC50) value of 9.95 μM, which was superior to that of ribavirin (the positive control, IC50 = 11.43 μM). Moreover, 38a also has inhibitory activity against coronavirus 229E with an IC50 of 30.82 μM. In addition, compounds 42 and 46f exhibit an 82% inhibition rate against vesicular stomatitis virus at a concentration of 20 μM and hardly induce cytotoxicity in host cells. This work demonstrates the feasibility of designing nucleoside analogues with “ring‐opening” bases and suggests the “ring‐opening” nucleosides may have greater polarity, and designing prodrugs is an important aspect of optimizing their antiviral activity. Future research should focus on enhancing the conformational restriction of open‐loop bases to mimic Watson‐Crick base pairing better and improve antiviral activity.

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Remdesivir inhibits the polymerases of the novel filoviruses Lloviu and Bombali virus

Cited by 12 publications

References 39 publications

Recombinant Lloviu virus as a tool to study viral replication and host responses

Recombinant Lloviu virus as a tool to study viral replication and host responses

Recombinant Lloviu virus as a model to study inaccessible zoonotic viruses

Design of novel broad‐spectrum antiviral nucleoside analogues using natural bases ring‐opening strategy

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