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Remdesivir was shown to inhibit RNA-dependent RNA-polymerases (RdRp) from distinct viral families such as from
Filoviridae
(Ebola) and
Coronaviridae
(SARS-CoV, SARS-CoV-2, MERS). In this study, we tested the ability of remdesivir to inhibit RdRps from the
Flaviviridae
family. Instead of remdesivir, we used the active species that is produced in cells from remdesivir, the appropriate triphosphate, which could be directly tested
in vitro
using recombinant flaviviral polymerases. Our results show that remdesivir can efficiently inhibit RdRps from viruses causing severe illnesses such as Yellow fever, West Nile fever, Japanese and Tick-borne encephalitis, Zika and Dengue. Taken together, this study demonstrates that remdesivir or its derivatives have the potential to become a broad-spectrum antiviral agent effective against many RNA viruses.
SARS-CoV-2 has caused an extensive pandemic of COVID-19 all around the world. Key viral enzymes are suitable molecular targets for the development of new antivirals against SARS-CoV-2 which could represent potential treatments of the corresponding disease. With respect to its essential role in the replication of viral RNA, RNA-dependent RNA polymerase (RdRp) is one of the prime targets. HeE1-2Tyr and related derivatives were originally discovered as inhibitors of the RdRp of flaviviruses. Here, we present that these pyridobenzothiazole derivatives also significantly inhibit SARS-CoV-2 RdRp, as demonstrated using both polymerase- and cell-based antiviral assays.
A series of 7-deazaadenine ribonucleosides bearing alkyl, alkenyl,
alkynyl, aryl, or hetaryl groups at position 7 as well as their 5′-O-triphosphates and two types of monophosphate prodrugs
(phosphoramidates and S-acylthioethanol esters) were
prepared and tested for antiviral activity against selected RNA viruses
(Dengue, Zika, tick-borne encephalitis, West Nile, and SARS-CoV-2).
The modified triphosphates inhibited the viral RNA-dependent RNA polymerases
at micromolar concentrations through the incorporation of the modified
nucleotide and stopping a further extension of the RNA chain. 7-Deazaadenosine
nucleosides bearing ethynyl or small hetaryl groups at position 7
showed (sub)micromolar antiviral activities but significant cytotoxicity,
whereas the nucleosides bearing bulkier heterocycles were still active
but less toxic. Unexpectedly, the monophosphate prodrugs were similarly
or less active than the corresponding nucleosides in the in
vitro antiviral assays, although the bis(S-acylthioethanol) prodrug 14h was transported to the
Huh7 cells and efficiently released the nucleoside monophosphate.
We have identified seven putative guanine quadruplexes (G4) in the RNA genome of tick-borne encephalitis virus (TBEV), a flavivirus causing thousands of human infections and numerous deaths every year. The formation of G4s was confirmed by biophysical methods on synthetic oligonucleotides derived from the predicted TBEV sequences. TBEV-5, located at the NS4b/NS5 boundary and conserved among all known flaviviruses, was tested along with its mutated variants for interactions with a panel of known G4 ligands, for the ability to affect RNA synthesis by the flaviviral RNA-dependent RNA polymerase (RdRp) and for effects on TBEV replication fitness in cells. G4-stabilizing TBEV-5 mutations strongly inhibited RdRp RNA synthesis and exhibited substantially reduced replication fitness, different plaque morphology and increased sensitivity to G4-binding ligands in cell-based systems. In contrast, strongly destabilizing TBEV-5 G4 mutations caused rapid reversion to the wild-type genotype. Our results suggest that there is a threshold of stability for G4 sequences in the TBEV genome, with any deviation resulting in either dramatic changes in viral phenotype or a rapid return to this optimal level of G4 stability. The data indicate that G4s are critical elements for efficient TBEV replication and are suitable targets to tackle TBEV infection.
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