Cell line-dependent activation and antiviral activity of T-1105, the non-fluorinated analogue of T-705 (favipiravir)

Huchting, Johanna; Vanderlinden, Evelien; Berwaer, Ria Van; Meier, Chris; Naesens, Lieve

doi:10.1016/j.antiviral.2019.04.002

Cited by 28 publications

(28 citation statements)

References 25 publications

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“…3a) into RNA. T-1105 shows improved potency against influenza virus in certain cell lines and is reportedly more stable than T-705 in the RTP form used in enzyme assays [20][21][22] . The MoA for these compounds is currently controversial.…”

Section: Resultsmentioning

confidence: 99%

Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis

et al. 2020

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The ongoing Corona Virus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emphasized the urgent need for antiviral therapeutics. The viral RNA-dependent-RNA-polymerase (RdRp) is a promising target with polymerase inhibitors successfully used for the treatment of several viral diseases. We demonstrate here that Favipiravir predominantly exerts an antiviral effect through lethal mutagenesis. The SARS-CoV RdRp complex is at least 10-fold more active than any other viral RdRp known. It possesses both unusually high nucleotide incorporation rates and high-error rates allowing facile insertion of Favipiravir into viral RNA, provoking C-to-U and G-to-A transitions in the already low cytosine content SARS-CoV-2 genome. The coronavirus RdRp complex represents an Achilles heel for SARS-CoV, supporting nucleoside analogues as promising candidates for the treatment of COVID-19.

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Section: Resultsmentioning

confidence: 99%

Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis

et al. 2020

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“…Moreover, T-1105 has demonstrated greater potency to inhibit influenza virus in MDCK cell-based assays and the corresponding ribonucleoside 5’-triphosphate (T-1105-RTP) competes with the purines ATP or GTP during viral RNA synthesis more efficiently than T-705-RTP, which has been shown in the context of human norovirus, 145 influenza virus 167 as well as SARS-CoV 146 polymerase. As mentioned above, however, inefficient metabolic activation to its triphosphate form also limits T-1105’s antiviral potency and hence, this compound suffers from drastic differences in efficacy when studied in different cell types, 165 which may somewhat conceal potential broad-spectrum antiviral potency. As mentioned above, both RBV as well as the active forms of T-705 and T-1105 contain an unmodified ribo -glycon.…”

Section: Targeting Viral Rna Synthesis With Direct-acting Antiviral Nmentioning

confidence: 99%

Targeting viral genome synthesis as broad-spectrum approach against RNA virus infections

Huchting

2020

Antivir Chem Chemother

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Zoonotic spillover, i.e. pathogen transmission from animal to human, has repeatedly introduced RNA viruses into the human population. In some cases, where these viruses were then efficiently transmitted between humans, they caused large disease outbreaks such as the 1918 flu pandemic or, more recently, outbreaks of Ebola and Coronavirus disease. These examples demonstrate that RNA viruses pose an immense burden on individual and public health with outbreaks threatening the economy and social cohesion within and across borders. And while emerging RNA viruses are introduced more frequently as human activities increasingly disrupt wild-life eco-systems, therapeutic or preventative medicines satisfying the “one drug-multiple bugs”-aim are unavailable. As one central aspect of preparedness efforts, this review digs into the development of broadly acting antivirals via targeting viral genome synthesis with host- or virus-directed drugs centering around nucleotides, the genomes’ universal building blocks. Following the first strategy, selected examples of host de novo nucleotide synthesis inhibitors are presented that ultimately interfere with viral nucleic acid synthesis, with ribavirin being the most prominent and widely used example. For directly targeting the viral polymerase, nucleoside and nucleotide analogues (NNAs) have long been at the core of antiviral drug development and this review illustrates different molecular strategies by which NNAs inhibit viral infection. Highlighting well-known as well as recent, clinically promising compounds, structural features and mechanistic details that may confer broad-spectrum activity are discussed. The final part addresses limitations of NNAs for clinical development such as low efficacy or mitochondrial toxicity and illustrates strategies to overcome these.

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“…Similarly, 3-hydroxy-2-pyrazinecarboxamide (T1105) which is a structural analogue of T705 has shown a good antiviral activity against influenza virus [27] CONTACT Yunusa Umar umar − y@jic.edu.sa Department of Chemical and Process Engineering Technology, Jubail Industrial College, PO Box 10099, Jubail Industrial City 31961, Saudi Arabia Supplemental data for this article can be accessed here. https://doi.org/10.1080/16583655.2020.1848982…”

Section: Introductionmentioning

confidence: 99%

Theoretical studies of the rotational and tautomeric states, electronic and spectroscopic properties of favipiravir and its structural analogues: a potential drug for the treatment of COVID-19

Umar

2020

Journal of Taibah University for Science

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Cell line-dependent activation and antiviral activity of T-1105, the non-fluorinated analogue of T-705 (favipiravir)

Cited by 28 publications

References 25 publications

Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis

Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis

Targeting viral genome synthesis as broad-spectrum approach against RNA virus infections

Theoretical studies of the rotational and tautomeric states, electronic and spectroscopic properties of favipiravir and its structural analogues: a potential drug for the treatment of COVID-19

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