► Favipiravir (T-705) is an influenza drug in clinical development. ► Favipiravir inhibits (murine) norovirus-induced CPE and viral RNA synthesis. ► Favipiravir inhibits viral replication at a time ...point that coincides with the onset of viral RNA synthesis.
Human noroviruses are the primary cause of foodborne gastroenteritis. Potent and safe inhibitors are needed for the treatment/prophylaxis of norovirus infections. We demonstrate that Favipiravir T-705, a drug in advanced clinical development for the treatment of infections with the influenza virus inhibits in vitro murine norovirus replication. Time-of-drug addition studies reveal that T-705 exerts its activity at a time-point that coincides with onset of viral RNA synthesis, which is in line with the viral polymerase as the presumed target.
The chikungunya virus (CHIKV) has become a substantial global health threat due to its massive re-emergence, the considerable disease burden and the lack of vaccines or therapeutics. We discovered a ...novel class of small molecules (1,2,3triazolo4,5-dpyrimidin-7(6H)-ones) with potent in vitro activity against CHIKV isolates from different geographical regions. Drug-resistant variants were selected and these carried a P34S substitution in non-structural protein 1 (nsP1), the main enzyme involved in alphavirus RNA capping. Biochemical assays using nsP1 of the related Venezuelan equine encephalitis virus revealed that the compounds specifically inhibit the guanylylation of nsP1. This is, to the best of our knowledge, the first report demonstrating that the alphavirus capping machinery is an excellent antiviral drug target. Considering the lack of options to treat CHIKV infections, this series of compounds with their unique (alphavirus-specific) target offers promise for the development of therapy for CHIKV infections.
► A panel of reference antiviral molecules was screened against norovirus. ► 2′-C-methylcytidine (2CMC) was identified as an inhibitor of the replication of (murine) norovirus. ► 2CMC inhibits ...virus-induced CPE formation, the production of infectious viruses and viral RNA synthesis. ► The antiviral effect coincides with the onset of viral RNA synthesis, suggesting the viral polymerase as target. ► When combined with ribavirin a marked antagonistic activity is observed.
We here report on the activity of 2′-C-methylcytidine (2CMC) a nucleoside polymerase inhibitor of the hepatitis C virus (HCV) on the in vitro replication of (murine) norovirus (MNV). 2CMC inhibits (i) virus-induced CPE formation, (ii) viral RNA synthesis and (iii) infectious progeny formation with EC50 values of ∼2μM. 2CMC acts at a time-point that coincides with the onset of viral RNA synthesis. Even following 30 passages of selective pressure no MNV-resistant virus was selected, which is in line with the high barrier to resistance of the nucleoside analogue for HCV. When combined with the broad-spectrum RNA virus inhibitor ribavirin, a marked antagonistic activity was observed indicating that these molecules should not be combined for the treatment of norovirus infections. Our results suggest that 2′-C-methyl nucleoside analogues should be further explored for the treatment and prophylaxis of norovirus infections.
Although direct-acting antiviral agents (DAAs) have markedly improved the outcome of treatment in chronic HCV infection, there continues to be an unmet medical need for improved therapies in ...difficult-to-treat patients as well as liver graft infection. Viral entry is a promising target for antiviral therapy.
Aiming to explore the role of entry inhibitors for future clinical development, we investigated the antiviral efficacy and toxicity of entry inhibitors in combination with DAAs or other host-targeting agents (HTAs). Screening a large series of combinations of entry inhibitors with DAAs or other HTAs, we uncovered novel combinations of antivirals for prevention and treatment of HCV infection.
Combinations of DAAs or HTAs and entry inhibitors including CD81-, scavenger receptor class B type I (SR-BI)- or claudin-1 (CLDN1)-specific antibodies or small-molecule inhibitors erlotinib and dasatinib were characterised by a marked and synergistic inhibition of HCV infection over a broad range of concentrations with undetectable toxicity in experimental designs for prevention and treatment both in cell culture models and in human liver-chimeric uPA/SCID mice.
Our results provide a rationale for the development of antiviral strategies combining entry inhibitors with DAAs or HTAs by taking advantage of synergy. The uncovered combinations provide perspectives for efficient strategies to prevent liver graft infection and novel interferon-free regimens.
There are virtually no antiviral drugs available for the treatment of infections with RNA viruses. This is particularly worrisome since most of the highly pathogenic and emerging viruses are, and ...will likely continue to be, RNA viruses. These viruses can cause acute, severe illness, including severe respiratory disease, hemorrhagic fever and encephalitis, with a high case fatality rate. It is important to have potent and safe drugs at hand that can be used for the treatment or prophylaxis of such infections. Drugs approved for the treatment of RNA virus infections (other than HIV) are the influenza M2 channel inhibitors, amantadine and rimantadine; the influenza neuraminidase inhibitors, oseltamivir and zanamivir, and ribavirin for the treatment of infections with respiratory syncytial virus and hepatitis C virus. The molecular mechanism(s) by which ribavirin inhibits viral replication, such as depletion of intracellular GTP pools and induction of error catastrophe, may not readily allow the design of analogues that are more potent/selective than the parent drug. Highly pathogenic RNA viruses belong to a variety of virus families, each having a particular replication strategy, thus offering a wealth of potential targets to selectively inhibit viral replication. We here provide a non-exhaustive review of potential experimental strategies, using small molecules, to inhibit the replication of several RNA viruses. Other approaches, such as the use of interferon or other host-response modifiers, immune serum or neutralizing antibodies, are not addressed in this review.
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