Prodrugs of the Phosphoribosylated Forms of Hydroxypyrazinecarboxamide Pseudobase T-705 and Its De-Fluoro Analogue T-1105 as Potent Influenza Virus Inhibitors

Huchting, Johanna; Vanderlinden, Evelien; Winkler, Mathias; Nasser, Hiba; Naesens, Lieve; Meier, Chris

doi:10.1021/acs.jmedchem.8b00617

Cited by 38 publications

(85 citation statements)

References 61 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 – 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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“…T-1105-ribose-TP (RTP), the 5'-triphosphate of the non-fluorinated derivative of T-705ribose, was synthesized as described previously 21 following the iterative route from mono-via di-to triphosphate with minor modifications. To overcome low solubility of T-1105-250 ribonucleotides in organic solvent, the 2'-and 3'-acetyl groups were kept until the final TPsynthesis and were then cleaved by treatment with base.…”

Section: Nucleotide Substratesmentioning

confidence: 99%

“…1a,b) into RNA. T-1105 shows improved potency against influenza virus in certain cell lines and is more stable than T-705 in the RTP form used in enzyme assays [19][20][21] . The MoA for these compounds is currently controversial.…”

mentioning

confidence: 99%

Favipiravir strikes the SARS-CoV-2 at its Achilles heel, the RNA polymerase

Shannon

Selisko

et al. 2020

Preprint

101

113

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The ongoing Corona Virus Disease 2019 pandemic, caused by severe 20 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. Here we show that Favipiravir exerts an antiviral effect as a nucleotide analogue through a combination of chain termination, slowed RNA synthesis and lethal mutagenesis. The SARS-CoV RdRp 25 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 30 COVID-19.2 Coronaviruses (CoV) are large genome, positive-strand RNA viruses of the order 35 Nidovirales that have recently attracted global attention due to the ongoing COVID-19 pandemic. Despite significant efforts to control its spread, SARS-CoV-2 has caused substantial health and economic burden, emphasizing the immediate need for antiviral treatments. As with all positive strand RNA viruses, an RdRp lies at the core of the viral replication machinery and for CoVs this is the nsp12 protein. The pivotal role of nsp12 in the viral life-cycle, lack of host 40 homologues and high level of sequence and structural conservation makes it an optimal target for therapeutics. However, there has been remarkably little biochemical characterization of nsp12 and a lack of fundamental data to guide the design of antiviral therapeutics and study their mechanism of action (MoA). A promising class of RdRp inhibitors are nucleoside analogues (NAs), small molecule drugs that are metabolized intracellularly into their active ribonucleoside 45 5'-triphosphate (RTP) forms and incorporated into the nascent viral RNA by error-prone viral RdRps. This can disrupt RNA synthesis directly via chain termination, or can lead to the accumulation of deleterious mutations in the viral genome. For CoVs, the situation is complicated by the post-replicative repair capacity provided by the nsp14 exonuclease (ExoN) that is essential for maintaining the integrity of their large ~30 kb genomes 1-3 . Nsp14 has been 50 shown to remove certain NAs after insertion by the RdRp into the nascent RNA, thus reducing their antiviral effects 4-6 . Despite this, several NAs currently being used for the treatment of other viral infections have been identified as potential anti-CoV candidates 7-9 . Among these is the purine base analogue T-705 (Favipiravir, Avigan, Extended data Fig. 1a,b) that has broadspectrum activity against a number of RNA viruses and is currently licensed in Japan for use in 55

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“…In a retrospective clinical study during the outbreak of Ebola virus, patients who received T-705 had a significant viral load reduction compared with the control group (Bai et al 2016). Recently, favipiravir and related structures have attracted extensive attentions in the field of antiviral and antiparasitic research (Gao et al 2018;Huchting et al 2018;Huchting et al 2017;Klejch et al 2018;Plebanek et al 2017;Wang et al 2016).…”

Section: Introductionmentioning

confidence: 99%

The complete synthesis of favipiravir from 2-aminopyrazine

Guo

et al. 2019

Chem. Pap.

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Favipiravir was first synthesized from an inexpensive and commercially available starting material, 2-aminopyrazine. The preferred route embedded within Scheme 4 consisted of seven steps, and was highlighted by the novel and efficient synthesis of 3,6-dichloropyrazine-2-carbonitrile 8. This intermediate was prepared in four successive steps which were regioselective chlorination of the pyrazine ring, bromination, Pd-catalyzed cyanation, and Sandmeyer diazotization/chlorination. This protocol eliminated the hazardous POCl 3 of previous synthetic methods and offered a better yield (48%) which was 1.3-fold higher than a recently published procedure. From intermediate 8, the subsequent nucleophilic fluorination, nitrile hydration and hydroxyl substitution efficiently afforded the target product. Another synthetic approach with the same starting material was also investigated to bypass the allergy-causing dichloro intermediate 8. However, the key step of monofluorination at the pyrazine C6 position of intermediate 19 or 22 was not achieved.

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Prodrugs of the Phosphoribosylated Forms of Hydroxypyrazinecarboxamide Pseudobase T-705 and Its De-Fluoro Analogue T-1105 as Potent Influenza Virus Inhibitors

Cited by 38 publications

References 61 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

Favipiravir strikes the SARS-CoV-2 at its Achilles heel, the RNA polymerase

The complete synthesis of favipiravir from 2-aminopyrazine

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