The aim of this review is to follow the history of studies on endemiv arboviruses and the diseases they cause which were detected in the Czech lands (Bohemia, Moravia and Silesia (i.e., the Czech Republic)). The viruses involve tick-borne encephalitis, West Nile and Usutu flaviviruses; the Sindbis alphavirus; Ťahyňa, Batai, Lednice and Sedlec bunyaviruses; the Uukuniemi phlebovirus; and the Tribeč orbivirus. Arboviruses temporarily imported from abroad to the Czech Republic have been omitted. This brief historical review includes a bibliography of all relevant papers.

• Keywords
• arthropods, birds, mammals, mosquitoes, ticks,
• MeSH
• Arbovirus Infections history   MeSH
• Arboviruses physiology   MeSH
• History, 20th Century MeSH
• History, 21st Century MeSH
• Humans MeSH
• Animals MeSH
• Check Tag
• History, 20th Century MeSH
• History, 21st Century MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Historical Article MeSH
• Review MeSH
• Geographicals
• Czech Republic epidemiology   MeSH

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.

• Keywords
• Flavivirus, Inhibitor, RNA-dependent RNA polymerase, Remdesivir,
• MeSH
• Adenosine Triphosphate analogs & derivatives   chemistry   pharmacology   MeSH
• Antiviral Agents chemistry   pharmacology   MeSH
• Betacoronavirus drug effects   enzymology   MeSH
• COVID-19 MeSH
• COVID-19 Drug Treatment MeSH
• Flavivirus drug effects   enzymology   MeSH
• Inhibitory Concentration 50 MeSH
• Coronavirus Infections drug therapy   virology   MeSH
• Humans MeSH
• Pandemics MeSH
• RNA-Dependent RNA Polymerase antagonists & inhibitors   metabolism   MeSH
• RNA Viruses drug effects   enzymology   MeSH
• SARS-CoV-2 MeSH
• Pneumonia, Viral drug therapy   virology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenosine Triphosphate MeSH
• Antiviral Agents MeSH
• GS-441524 triphosphate MeSH Browser
• RNA-Dependent RNA Polymerase MeSH

The adenosine analogue galidesivir (BCX4430), a broad-spectrum RNA virus inhibitor, has entered a phase 1 clinical safety and pharmacokinetics study in healthy subjects and is under clinical development for treatment of Ebola and yellow fever virus infections. Moreover, galidesivir also inhibits the reproduction of tick-borne encephalitis virus (TBEV) and numerous other medically important flaviviruses. Until now, studies of this antiviral agent have not yielded resistant viruses. Here, we demonstrate that an E460D substitution in the active site of TBEV RNA-dependent RNA polymerase (RdRp) confers resistance to galidesivir in cell culture. Galidesivir-resistant TBEV exhibited no cross-resistance to structurally different antiviral nucleoside analogues, such as 7-deaza-2'-C-methyladenosine, 2'-C-methyladenosine, and 4'-azido-aracytidine. Although the E460D substitution led to only a subtle decrease in viral fitness in cell culture, galidesivir-resistant TBEV was highly attenuated in vivo, with a 100% survival rate and no clinical signs observed in infected mice. Furthermore, no virus was detected in the sera, spleen, or brain of mice inoculated with the galidesivir-resistant TBEV. Our results contribute to understanding the molecular basis of galidesivir antiviral activity, flavivirus resistance to nucleoside inhibitors, and the potential contribution of viral RdRp to flavivirus neurovirulence.IMPORTANCE Tick-borne encephalitis virus (TBEV) is a pathogen that causes severe human neuroinfections in Europe and Asia and for which there is currently no specific therapy. We have previously found that galidesivir (BCX4430), a broad-spectrum RNA virus inhibitor, which is under clinical development for treatment of Ebola and yellow fever virus infections, has a strong antiviral effect against TBEV. For any antiviral drug, it is important to generate drug-resistant mutants to understand how the drug works. Here, we produced TBEV mutants resistant to galidesivir and found that the resistance is caused by a single amino acid substitution in an active site of the viral RNA-dependent RNA polymerase, an enzyme which is crucial for replication of the viral RNA genome. Although this substitution led only to a subtle decrease in viral fitness in cell culture, galidesivir-resistant TBEV was highly attenuated in a mouse model. Our results contribute to understanding the molecular basis of galidesivir antiviral activity.

• Keywords
• BCX4430, attenuation, drug resistance, galidesivir, mutation, tick-borne encephalitis virus,
• MeSH
• Adenine analogs & derivatives   chemistry   pharmacology   MeSH
• Adenosine analogs & derivatives   MeSH
• Alleles MeSH
• Drug Resistance, Microbial MeSH
• Antiviral Agents chemistry   pharmacology   MeSH
• Cell Line MeSH
• Genotype MeSH
• Encephalitis, Tick-Borne drug therapy   virology   MeSH
• Disease Models, Animal MeSH
• Mutation * MeSH
• Mice MeSH
• Pyrrolidines chemistry   pharmacology   MeSH
• Amino Acid Substitution * MeSH
• Drug Resistance, Viral * MeSH
• Viral Nonstructural Proteins genetics   MeSH
• Encephalitis Viruses, Tick-Borne drug effects   physiology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenine MeSH
• Adenosine MeSH
• Antiviral Agents MeSH
• galidesivir MeSH Browser
• Pyrrolidines MeSH
• Viral Nonstructural Proteins MeSH

West Nile virus (WNV) is a medically important emerging arbovirus causing serious neuroinfections in humans and against which no approved antiviral therapy is currently available. In this study, we demonstrate that 2'-C-methyl- or 4'-azido-modified nucleosides are highly effective inhibitors of WNV replication, showing nanomolar or low micromolar anti-WNV activity and negligible cytotoxicity in cell culture. One representative of C2'-methylated nucleosides, 7-deaza-2'-C-methyladenosine, significantly protected WNV-infected mice from disease progression and mortality. Twice daily treatment at 25 mg/kg starting at the time of infection resulted in 100% survival of the mice. This compound was highly effective, even if the treatment was initiated 3 days postinfection, at the time of a peak of viremia, which resulted in a 90% survival rate. However, the antiviral effect of 7-deaza-2'-C-methyladenosine was absent or negligible when the treatment was started 8 days postinfection (i.e., at the time of extensive brain infection). The 4'-azido moiety appears to be another important determinant for highly efficient inhibition of WNV replication in vitro However, the strong anti-WNV effect of 4'-azidocytidine and 4'-azido-aracytidine was cell type dependent and observed predominantly in porcine kidney stable (PS) cells. The effect was much less pronounced in Vero cells. Our results indicate that 2'-C-methylated or 4'-azidated nucleosides merit further investigation as potential therapeutic agents for treating WNV infections as well as infections caused by other medically important flaviviruses.

• Keywords
• West Nile virus, antiviral agents, flavivirus, nucleoside analogs,
• MeSH
• Antiviral Agents therapeutic use   MeSH
• Cell Line MeSH
• Chlorocebus aethiops MeSH
• Disease Models, Animal MeSH
• Mice, Inbred BALB C MeSH
• Mice MeSH
• Swine MeSH
• Disease Progression MeSH
• Virus Replication drug effects   MeSH
• RNA-Dependent RNA Polymerase antagonists & inhibitors   MeSH
• Tubercidin analogs & derivatives   therapeutic use   MeSH
• Vero Cells MeSH
• Viremia drug therapy   MeSH
• West Nile virus drug effects   genetics   MeSH
• West Nile Fever drug therapy   pathology   virology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 7-deaza-2'-C-methyladenosine MeSH Browser
• Antiviral Agents MeSH
• RNA-Dependent RNA Polymerase MeSH
• Tubercidin MeSH

Nucleoside analogs represent the largest class of small molecule-based antivirals, which currently form the backbone of chemotherapy of chronic infections caused by HIV, hepatitis B or C viruses, and herpes viruses. High antiviral potency and favorable pharmacokinetics parameters make some nucleoside analogs suitable also for the treatment of acute infections caused by other medically important RNA and DNA viruses. This review summarizes available information on antiviral research of nucleoside analogs against arthropod-borne members of the genus Flavivirus within the family Flaviviridae, being primarily focused on description of nucleoside inhibitors of flaviviral RNA-dependent RNA polymerase, methyltransferase, and helicase/NTPase. Inhibitors of intracellular nucleoside synthesis and newly discovered nucleoside derivatives with high antiflavivirus potency, whose modes of action are currently not completely understood, have drawn attention. Moreover, this review highlights important challenges and complications in nucleoside analog development and suggests possible strategies to overcome these limitations.

• Keywords
• Nucleoside analog, antiviral agent, antiviral therapy, arthropod-borne flavivirus, inhibitor,
• MeSH
• Antiviral Agents chemistry   pharmacology   MeSH
• Culicidae virology   MeSH
• Flavivirus drug effects   MeSH
• Flavivirus Infections drug therapy   virology   MeSH
• Microbial Sensitivity Tests MeSH
• Molecular Structure MeSH
• Nucleosides chemistry   pharmacology   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antiviral Agents MeSH
• Nucleosides MeSH