The mechanism of resistance to favipiravir in influenza

Goldhill, Daniel H.; Velthuis, Aartjan J.W. te; Fletcher, Robert A.; Langat, Pinky; Zambon, Maria; Lackenby, Angie; Barclay, William

doi:10.1073/pnas.1811345115

Cited by 276 publications

(270 citation statements)

References 49 publications

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“…Favipiravir is converted to its active form, ribofuranosyl-5triphosphate, by host enzymes and inhibits viral RNA polymerase in the host cells. Only a few reports have indicated resistance to favipiravir in vitro (Delang et al, 2014;Goldhill et al, 2018). As shown in Tables 1, 2 favipiravir significantly inhibits SFTSV replication in vitro (Tani et al, 2016;Baba et al, 2017) and in vivo (Tani et al, 2016(Tani et al, , 2018Smee et al, 2018).…”

Section: Favipiravirmentioning

confidence: 97%

Antiviral Drugs Against Severe Fever With Thrombocytopenia Syndrome Virus Infection

Takayama-Ito

Saijo

2020

Front. Microbiol.

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Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by SFTS virus (SFTSV), which is a novel bunyavirus. SFTSV was first isolated from patients who presented with fever, thrombocytopenia, leukocytopenia, and multiorgan dysfunction in China. Subsequently, it was found to be widely distributed in Southeast Asia (Korea, Japan, and Vietnam). SFTSV can be transmitted not only from ticks but also from domestic animals, companion animals, and humans. Because the case fatality rate of SFTS is high (6-30%), development of specific and effective treatment for SFTS is required. Studies of potential antiviral drugs for SFTS-specific therapy have been conducted on existing or newly discovered agents in vitro and in vivo, with ribavirin and favipiravir being the most promising candidates. While animal experiments and retrospective studies have demonstrated the limited efficacy of ribavirin, it was also speculated that ribavirin would be effective in patients with a viral load <1 × 10 6 copies/mL. Favipiravir showed higher efficacy than ribavirin against SFTSV in in vitro assays and greater efficacy in animal models, even administrated 3 days after the virus inoculation. Although clinical trials evaluating the efficacy of favipiravir in SFTS patients in Japan are underway, this has yet to be confirmed. Other drugs, including hexachlorophene, calcium channel blockers, 2 ′ -fluoro-2 ′ -deoxycytidine, caffeic acid, amodiaquine, and interferons, have also been evaluated for their inhibitory efficacy against SFTSV. Among them, calcium channel blockers are promising because in addition to their efficacy in vitro and in vivo, retrospective clinical data have indicated that nifedipine, one of the calcium channel blockers, reduced the case fatality rate by >5-fold. Although further research is necessary to develop SFTS-specific therapy, considerable progress has been achieved in this area. Here we summarize and discuss recent advances in antiviral drugs against SFTSV.Keywords: severe fever with thrombocytopenia syndrome, severe fever with thrombocytopenia syndrome virus, antiviral, ribavirin, favipiravir Frontiers in Microbiology | www.frontiersin.org

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Section: Favipiravirmentioning

confidence: 97%

Antiviral Drugs Against Severe Fever With Thrombocytopenia Syndrome Virus Infection

Takayama-Ito

Saijo

2020

Front. Microbiol.

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“…Because both viruses are RNA virus depending on RNA-dependent RNA polymerase (RdRp) to replicate, the RdRp inhibitor Arbidol (common name for Umifenovir) approved for influenza in Russia and China has been proposed as a standard care option for COVID-19, mainly based on its mechanism-of-action (MoA) and its effects in treating influenza-associated pneumonia. [5][6][7] Favipiravir, an antiviral drug targeting RdRP, 8 approved in Japan for influenza, has an IC50 of 0.013-0.48 ug/ml for influenza A. Comparing this with the EC50 of 2.7-13.8 ug/ml of Arbidol, 9 we consider Favipiravir might serve as a potential candidate to treat COVID-19.…”

Section: Introductionmentioning

confidence: 97%

Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial

Chen

Zhang

Huang

et al. 2020

Preprint

690

737

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BackgroundNo clinically proven effective antiviral strategy exists for the epidemic Coronavirus Disease 2019 . MethodsWe conducted a prospective, randomized, controlled, open-label multicenter trial involving adult patients with COVID-19. Patients were randomly assigned in a 1:1 ratio to receive conventional therapy plus Umifenovir (Arbidol) (200mg*3/day) or Favipiravir (1600mg*2/first day followed by 600mg*2/day) for 10 days. The primary outcome was clinical recovery rate of Day 7. Latency to relief for pyrexia and cough, the rate of auxiliary oxygen therapy (AOT) or noninvasive mechanical ventilation (NMV) were the secondary outcomes. Safety data were collected for 17 days.

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“…Leading examples are at his point the pyrazinecarboxamide compounds T-705 (favipiravir; [2,7,48]), T-1105 and T-1106, which are broad-spectrum viral RNA polymerase inhibitors, initially developed for the treatment of influenza virus, and found effective against bunyaviruses [21,54,59], alphaviruses [1], filoviruses [13] arenaviruses [125], paramyxoviruses [29], and flaviviruses [128]. A favipiravir resistance mechanism in influenza virus has been described [52]. Other potential broad-spectrum agents are remdesivir (GS-5734), another RNA polymerase inhibitor [137] active against filo-, corona-, and paramyxoviruses [88,129,130], FGI-106 with inhibitory activity against filo-, bunya-, and flaviviruses [8], galidesivir (BCX4430) with activity against filo-, bunya-, and flaviviruses [39,143,145], N 4 -hydroxycytidine (NHC) inhibiting influenza-, paramyxo-, flavi-, corona-, as well as alphaviruses [152], and 2′fluoro-2′-deoxycytidine (2′-FdC), which was reported to inhibit various viruses in vitro, including Borna virus, HCV, Lassa virus, certain herpes viruses, and which also inhibits influenza viruses in mice [134].…”

Section: Synergy Through Combination and The Use Of Broad-spectrum Anmentioning

confidence: 99%

Antivirals in medical biodefense

et al. 2020

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The viruses historically implicated or currently considered as candidates for misuse in bioterrorist events are poxviruses, filoviruses, bunyaviruses, orthomyxoviruses, paramyxoviruses and a number of arboviruses causing encephalitis, including alpha-and flaviviruses. All these viruses are of concern for public health services when they occur in natural outbreaks or emerge in unvaccinated populations. Recent events and intelligence reports point to a growing risk of dangerous biological agents being used for nefarious purposes. Public health responses effective in natural outbreaks of infectious disease may not be sufficient to deal with the severe consequences of a deliberate release of such agents. One important aspect of countermeasures against viral biothreat agents are the antiviral treatment options available for use in post-exposure prophylaxis. These issues were adressed by the organizers of the 16th Medical Biodefense Conference, held in Munich in 2018, in a special session on the development of drugs to treat infections with viruses currently perceived as a threat to societies or associated with a potential for misuse as biothreat agents. This review will outline the state-of-the-art methods in antivirals research discussed and provide an overview of antiviral compounds in the pipeline that are already approved for use or still under development.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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The mechanism of resistance to favipiravir in influenza

Cited by 276 publications

References 49 publications

Antiviral Drugs Against Severe Fever With Thrombocytopenia Syndrome Virus Infection

Antiviral Drugs Against Severe Fever With Thrombocytopenia Syndrome Virus Infection

Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial

Antivirals in medical biodefense

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