Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral

Delang, Leen; Segura, Nidya Alexandra; Taş, Ali; Quérat, Gilles; Pastorino, Boris; Froeyen, Mathy; Dallmeier, Kai; Jochmans, Dirk; Herdewijn, Piet; Bello, Felio J.; Snijder, Eric J.; Lamballerie, Xavier de; Martina, Benedict; Neyts, Johan; Hemert, Martijn J. van; Leyssen, Pieter

doi:10.1093/jac/dku209

Cited by 199 publications

(207 citation statements)

References 45 publications

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“…Our data indicate that T-705 does not induce lethal mutagenesis on HMPV genomes but does have a direct effect on the HMPV polymerase. This is in line with the activity against the influenza virus RNA-dependent RNA polymerase reported by Kiso et al (50) and with data reported for the chikungunya virus, in which a single mutation in the polymerase protein was sufficient to make the virus resistant to treatment (47). Although it is possible that T-705 interferes with viral morphogenesis at a late stage of the infectious cycle, T-705 is a nucleotide analog, and its mechanism of action is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerases of influenza virus and many other RNA viruses (21,23 (32,51).…”

Section: Discussionsupporting

confidence: 90%

“…Both direct inhibition of the polymerase and induction of lethal mutagenesis have been described (23,24,47,49). In the T-705-treated hamsters inoculated with HMPV, viral genomes were detected in all animals even when the animals were treated at high doses.…”

Section: Discussionmentioning

confidence: 95%

“…To investigate whether T-705 has a direct effect on the activity of the polymerase proteins of HMPV, as described for those of influenza virus and chikungunya virus (18,47), the inhibitory effect of T-705 on polymerase complex activity was evaluated by use of a minigenome system. Addition of DMSO alone (data not shown) or increasing concentrations of T-705 had no inhibitory effect on the expression of the constitutively expressed renilla luciferase or on the expression of a T7 promoter-driven firefly luciferase expression plasmid (Fig.…”

Section: Antiviral Activity Of T-705 Against Paramyxoviruses In Vitromentioning

confidence: 99%

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Antiviral Activity of Favipiravir (T-705) against a Broad Range of Paramyxoviruses In Vitro and against Human Metapneumovirus in Hamsters

Jochmans

Nieuwkoop

Smits

et al. 2016

Antimicrob Agents Chemother

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T he family Paramyxoviridae contains a number of viruses causing respiratory tract illnesses in humans, which together have a large clinical impact (1). Human metapneumovirus (HMPV), respiratory syncytial virus (RSV), and parainfluenza virus (PIV) infections are responsible for severe acute respiratory illnesses mainly in young children, but also in immunocompromised and elderly individuals, and are-together with the influenza viruses (family Orthomyxoviridae)-the primary viral causes of hospitalizations for severe respiratory tract disease (2-5). No licensed vaccines or effective antiviral treatments are available for these viruses. Measles virus, yet another paramyxovirus, is responsible for a devastating disease which the WHO committed to eradicate with the aid of effective vaccines. However, due to suboptimal immunization levels, resurgences in infections have been detected, and there is no effective antiviral treatment available for measles virusinfected patients (6-8). Paramyxoviruses are well known for their zoonotic potential: avian pneumovirus (AMPV) is the proposed avian ancestor of HMPV, and the avian Newcastle disease virus (NDV) can cause disease-primarily conjunctivitis-in humans (9-11). Multiple novel paramyxoviruses have been detected in bats, including close relatives of human viruses (12, 13), and henipaviruses continue to cause infections in humans in . No licensed vaccines or effective antiviral treatments are available for any of these viruses. The continuous burden of disease associated with human and zoonotic paramyxoviruses argues for the development of antiviral therapies with broad-spectrum activity against all paramyxoviruses.Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamine) is a pyrazine derivative that has demonstrated potent antiviral activity against multiple RNA viruses (18,19). Intracellular host enzymes act upon T-705, converting it to its active form, T-705-4-ribofuranosyl-5-triphosphate (T-705RTP) (20). T-705RTP functions as a purine nucleotide analog that selectively inhibits the RNA-dependent RNA polymerase (RdRp) or causes lethal mutagenesis upon incorporation into the viral RNA (21-24). T-705 is presently in clinical development as an influenza virus inhibitor in Japan (new drug application filed) and the United States (phase 3 clinical trial) (18). Antiviral activity has been demonstrated against a broad range of negative-strand RNA viruses, such as members of the Picorna-, , and positive-strand RNA viruses, such as the Noro-and Flavivirus genera (31, 32). Here we evaluated the activity of T-705 against a broad range of paramyxoviruses in vitro and against HMPV in hamsters. MATERIALS AND METHODS Cells

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 95%

Section: Antiviral Activity Of T-705 Against Paramyxoviruses In Vitromentioning

confidence: 99%

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Antiviral Activity of Favipiravir (T-705) against a Broad Range of Paramyxoviruses In Vitro and against Human Metapneumovirus in Hamsters

Jochmans

Nieuwkoop

Smits

et al. 2016

Antimicrob Agents Chemother

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“…Taken together, the in vivo results show dual roles of berberine as an antiviral and an anti-inflammatory agent, and this is one of the few reports of an antiviral against CHIKV showing efficacy in a mouse model (3). Earlier, favipiravir was shown to protect against neurological complications and death in a mouse model of lethal CHIKV infection, which does not represent disease outcomes in the majority of CHIKV-infected patients (65). Interestingly, treatments were given either 24 h before infection or 4 h p.i., whereas in our study, berberine treatment was started only at 1 dpi.…”

Section: Discussionmentioning

confidence: 99%

The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling

Varghese

Thaa

Amrun

et al. 2016

J Virol

120

103

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Chikungunya virus (CHIKV) has infected millions of people in the tropical and subtropical regions since its reemergence in the last decade. We recently identified the nontoxic plant alkaloid berberine as an antiviral substance against CHIKV in a highthroughput screen. Here, we show that berberine is effective in multiple cell types against a variety of CHIKV strains, also at a high multiplicity of infection, consolidating the potential of berberine as an antiviral drug. We excluded any effect of this compound on virus entry or on the activity of the viral replicase. A human phosphokinase array revealed that CHIKV infection specifically activated the major mitogen-activated protein kinase (MAPK) signaling pathways extracellular signal-related kinase (ERK), p38 and c-Jun NH 2 -terminal kinase (JNK). Upon treatment with berberine, this virus-induced MAPK activation was markedly reduced. Subsequent analyses with specific inhibitors of these kinases indicated that the ERK and JNK signaling cascades are important for the generation of progeny virions. In contrast to specific MAPK inhibitors, berberine lowered virus-induced activation of all major MAPK pathways and resulted in a stronger reduction in viral titers. Further, we assessed the in vivo efficacy of berberine in a mouse model and measured a significant reduction of CHIKV-induced inflammatory disease. In summary, we demonstrate the efficacy of berberine as a drug against CHIKV and highlight the importance of the MAPK signaling pathways in the alphavirus infectious cycle. IMPORTANCEChikungunya virus (CHIKV) is a mosquito-borne virus that causes severe and persistent muscle and joint pain and has recently spread to the Americas. No licensed drug exists to counter this virus. In this study, we report that the alkaloid berberine is antiviral against different CHIKV strains and in multiple human cell lines. We demonstrate that berberine collectively reduced the virus-induced activation of cellular mitogen-activated protein kinase signaling. The relevance of these signaling cascades in the viral life cycle was emphasized by specific inhibitors of these kinase pathways, which decreased the production of progeny virions. Berberine significantly reduced CHIKV-induced inflammatory disease in a mouse model, demonstrating efficacy of the drug in vivo. Overall, this work makes a strong case for pursuing berberine as a potential anti-CHIKV therapeutic compound and for exploring the MAPK signaling pathways as antiviral targets against alphavirus infections. C hikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disease spread by Aedes mosquitoes and characterized by a sudden onset of febrile illness, nausea, headache, and most importantly, severe and persistent musculoskeletal pain (1). It reemerged in tropical Asia and Africa 1 decade ago and since 2013 has infected more than 1.5 million people in the Americas (2). So far, no licensed vaccine or antiviral treatment exists to counter this disease. Over the years, many research groups have focused on...

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“…To date, several studies have identified small-molecule inhibitors that inhibit CHIKV replication in cell culture (9)(10)(11)(12)(13)(14). Some nucleoside analogs, such as ribavirin, have also been shown to interfere with CHIKV replication.…”

mentioning

confidence: 99%

Characterization of β- d - N ⁴ -Hydroxycytidine as a Novel Inhibitor of Chikungunya Virus

Ehteshami

Tao

Zandi

et al. 2017

Antimicrob Agents Chemother

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Chikungunya virus (CHIKV) represents a reemerging global threat to human health. Recent outbreaks across Asia, Europe, Africa, and the Caribbean have prompted renewed scientific interest in this mosquito-borne alphavirus. There are currently no vaccines against CHIKV, and treatment has been limited to nonspecific antiviral agents, with suboptimal outcomes. Herein, we have identified ␤-D-N 4 -hydroxycytidine (NHC) as a novel inhibitor of CHIKV. NHC behaves as a pyrimidine ribonucleoside and selectively inhibits CHIKV replication in cell culture.

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Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral

Abstract: This study provides an important insight into the precise molecular mechanism by which favipiravir exerts its antiviral activity against (alpha)viruses, which may be of help in designing other potent broad-spectrum antivirals.

Cited by 199 publications

References 45 publications

Antiviral Activity of Favipiravir (T-705) against a Broad Range of Paramyxoviruses In Vitro and against Human Metapneumovirus in Hamsters

Antiviral Activity of Favipiravir (T-705) against a Broad Range of Paramyxoviruses In Vitro and against Human Metapneumovirus in Hamsters

The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling

Characterization of β- d - N ⁴ -Hydroxycytidine as a Novel Inhibitor of Chikungunya Virus

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Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral

Abstract: This study provides an important insight into the precise molecular mechanism by which favipiravir exerts its antiviral activity against (alpha)viruses, which may be of help in designing other potent broad-spectrum antivirals.

Cited by 199 publications

References 45 publications

Antiviral Activity of Favipiravir (T-705) against a Broad Range of Paramyxoviruses In Vitro and against Human Metapneumovirus in Hamsters

Antiviral Activity of Favipiravir (T-705) against a Broad Range of Paramyxoviruses In Vitro and against Human Metapneumovirus in Hamsters

The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling

Characterization of β- d - N 4 -Hydroxycytidine as a Novel Inhibitor of Chikungunya Virus

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Characterization of β- d - N ⁴ -Hydroxycytidine as a Novel Inhibitor of Chikungunya Virus