Host Factors Regulating the Influenza Virus Replication Machinery

Kirui, James; Tran, Vy M.; Mehle, Andrew

doi:10.21775/9781910190432.05

Cited by 5 publications

(4 citation statements)

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“…The possibility to suppress influenza virus by interfering with the purine or pyrimidine pathway was proposed for a few other enzymes [9,41] but our study is the first to identify the relevance of host (human) DHFR in antiviral therapy.…”

Section: Discussionmentioning

confidence: 99%

Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus

Tonelli

Naesens

Gazzarrini

et al. 2017

European Journal of Medicinal Chemistry

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We have identified a series of 1-aryl-4,6-diamino-1,2-dihydrotriazines, structurally related to the antimalarial drug cycloguanil, as new inhibitors of influenza A and B virus and respiratory syncytial virus (RSV) via targeting of the host dihydrofolate reductase (DHFR) enzyme. Most analogues proved active against influenza B virus in the low micromolar range, and the best compounds (11, 13, 14 and 16) even reached the sub-micromolar potency of zanamivir (EC = 0.060 μM), and markedly exceeded (up to 327 times) the antiviral efficacy of ribavirin. Activity was also observed for two influenza A strains, including a virus with the S31N mutant form of M2 proton channel, which is the most prevalent resistance mutation for amantadine. Importantly, the compounds displayed nanomolar activity against RSV and a superior selectivity index, since the ratio of cytotoxic to antiviral concentration was >10,000 for the three most active compounds 11, 14 and 16 (EC ∼0.008 μM), far surpassing the potency and safety profile of the licensed drug ribavirin (EC = 5.8 μM, SI > 43).

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Section: Discussionmentioning

confidence: 99%

Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus

Tonelli

Naesens

Gazzarrini

et al. 2017

European Journal of Medicinal Chemistry

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“…Viral polymerase activity during infection is regulated by both essential host co-factors as well as restriction factors that antagonize function (Kirui et al, 2016a). Acidic nuclear phosphoprotein 32 family member A (ANP32A, pp32) associates with the influenza A virus polymerase and stimulates vRNA synthesis from a cRNA template in vitro (Bradel-Tretheway et al, 2011; Sugiyama et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Differential Splicing of ANP32A in Birds Alters Its Ability to Stimulate RNA Synthesis by Restricted Influenza Polymerase

2018

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SUMMARY Adaptation of viruses to their hosts can result in specialization and a restricted host range. Species specific polymorphisms in the influenza virus polymerase restrict its host range during transmission from birds to mammals. ANP32A was recently identified as a cellular co-factor affecting polymerase adaption and activity. Avian influenza polymerases require ANP32A containing an insertion resulting from an exon duplication uniquely encoded in birds. Here we find that natural splice variants surrounding this exon create avian ANP32A proteins with distinct effects on polymerase activity. We demonstrate species-independent direct interactions between all ANP32A variants and the PB2 polymerase subunit. This interaction is enhanced in the presence of viral genomic RNA. In contrast, only avian ANP32A restored ribonucleoprotein complex assembly for a restricted polymerase by enhancing RNA synthesis. Our data suggest that ANP32A splicing variation among birds differentially affects viral replication, polymerase adaption, and the potential of avian hosts to be reservoirs.

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“…These data raise the possibility that adaptive mutations in PB2 may be important for intraor inter-molecular protein:protein interactions, which may also facilitate the conformational changes of the 627 domain. Viral polymerase activity during infection is regulated by both essential host co-factors as well as restriction factors that antagonize function (Kirui et al, 2016a). Acidic nuclear phosphoprotein 32 family member A (ANP32A, pp32) associates with the influenza A virus polymerase and stimulates vRNA synthesis from a cRNA template in vitro (Bradel-Tretheway et al, 2011;Sugiyama et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Differential splicing of ANP32A in birds alters its ability to stimulate RNA synthesis by restricted influenza polymerase

Baker

Ledwith

Mehle

2018

Preprint

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Adaptation of viruses to their host can result in specialization and a restricted host range. Species-specific polymorphisms in the influenza virus polymerase restrict its host range during transmission from birds to mammals. ANP32A was recently been identified as a cellular co-factor impacting polymerase adaption and activity. Avian influenza polymerases require ANP32A containing an insertion resulting from an exon duplication uniquely encoded in birds. Here we find that natural splice variants surrounding this exon create avian ANP32A proteins with distinct effects on polymerase activity. We demonstrate species-independent direct interactions between all ANP32A variants and the PB2 polymerase subunit. This interaction is enhanced in the presence of viral genomic RNA. In contrast, only avian ANP32A restored ribonucleoprotein complex assembly for a restricted polymerase by enhancing RNA synthesis. Our data suggest that ANP32A splicing variation amongst birds differentially impacts viral replication, polymerase adaption, and the potential of avian hosts to be reservoirs.

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Host Factors Regulating the Influenza Virus Replication Machinery

Cited by 5 publications

References 0 publications

Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus

Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus

Differential Splicing of ANP32A in Birds Alters Its Ability to Stimulate RNA Synthesis by Restricted Influenza Polymerase

Differential splicing of ANP32A in birds alters its ability to stimulate RNA synthesis by restricted influenza polymerase

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