Newer influenza antivirals, biotherapeutics and combinations

Hayden, Frederick G.

doi:10.1111/irv.12045

Cited by 61 publications

(67 citation statements)

References 175 publications

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“…These variants had amino acid substitutions in the PB2 gene, but not in other influenza virus polymerase complex genes, and these substitutions were rare in the database of naturally occurring human isolates. The issue of resistance to a direct-acting antiviral agent such as VX-787 is expected to some degree and can be managed in a treatment setting by proper dose selection and/or possibly by the combination of VX-787 with drugs in another class of antiviral agent such as the neuraminidase inhibitors (61). We observed in vitro synergy between VX-787 and oseltamivir, zanamivir, or favipiravir in this study.…”

Section: Discussionmentioning

confidence: 54%

Preclinical Activity of VX-787, a First-in-Class, Orally Bioavailable Inhibitor of the Influenza Virus Polymerase PB2 Subunit

Byrn

Jones

Bennett

et al. 2015

Antimicrob Agents Chemother

170

189

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h VX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support for the idea that VX-787 occupies the 7-methyl GTP (m 7 GTP) cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a K D (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC 50 (the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC 50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs). VX-787 was highly efficacious in both prophylaxis and treatment models of mouse influenza and was superior to the neuraminidase inhibitor, oseltamivir, including in delayed-start-to-treat experiments, with 100% survival at up to 96 h postinfection and partial survival in groups where the initiation of therapy was delayed up to 120 h postinfection. At different doses, VX-787 showed a 1-log to >5-log reduction in viral load (relative to vehicle controls) in mouse lungs. Overall, these favorable findings validate the PB2 subunit of the viral polymerase as a drug target for influenza therapy and support the continued development of VX-787 as a novel antiviral agent for the treatment of influenza infection. Influenza is a potentially deadly infectious disease that has imposed a substantial burden in terms of morbidity and mortality on human populations (1). Recent statistics suggest that, each year in the United States, 5% to 20% of the population becomes infected with influenza virus, with more than 200,000 hospitalizations for respiratory and heart-related complications and an annual mortality rate ranging from ϳ3,000 to 49,000 deaths (2, 3).Vaccination has become the mainstay of efforts to minimize the impact of seasonal influenza (4, 5), and while generally effective in healthy adults, it is often less effective in elderly individuals, and there have been recent examples where predictions of which viral strains to include have been inadequate (6, 7). Further, the 2009 H1N1 pandemic demonstrated that the logistics required to rapidly isolate and identify the correct strain and to produce enough vaccine worldwide was quite challenging (8-10). The continued incidence of human infection by avian influenza virus strains, namely, either the highly pathogenic H5N1 or H7N7 subtypes or the recently emerging low pathogenic H7N9 and H10N9 strains, represents an additional challenge for vaccine development strategies (11-15) Antiviral agents may be used for the prophylaxis of influenza virus infection (mainly in high-risk settings) or in a treatment modality for the reduction of illness duration. They may also provide an option for rapid deployment during a pandemic situati...

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Section: Discussionmentioning

confidence: 54%

Preclinical Activity of VX-787, a First-in-Class, Orally Bioavailable Inhibitor of the Influenza Virus Polymerase PB2 Subunit

Byrn

Jones

Bennett

et al. 2015

Antimicrob Agents Chemother

170

189

View full text Add to dashboard Cite

show abstract

“…However, these drugs are not available in many hospitals and are difficult to administer to patients who are mechanically ventilated, and moreover, the virus can also acquire resistance to them (2,3). Therefore, there is a need for developing newer antiviral agents against pH1N1and influenza viruses in general (4).…”

mentioning

confidence: 99%

Akt Inhibitor MK2206 Prevents Influenza pH1N1 Virus Infection In Vitro

Denisova

Söderholm

Virtanen

et al. 2014

Antimicrob Agents Chemother

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The influenza pH1N1 virus caused a global flu pandemic in 2009 and continues manifestation as a seasonal virus. Better understanding of the virus-host cell interaction could result in development of better prevention and treatment options. Here we show that the Akt inhibitor MK2206 blocks influenza pH1N1 virus infection in vitro. In particular, at noncytotoxic concentrations, MK2206 alters Akt signaling and inhibits endocytic uptake of the virus. Interestingly, MK2206 is unable to inhibit H3N2, H7N9, and H5N1 viruses, indicating that pH1N1 evolved specific requirements for efficient infection. Thus, Akt signaling could be exploited further for development of better therapeutics against pH1N1 virus.

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“…The increased number of NAI-resistant mutations might be overcome by other newer antivirals such as conjugated sialidases (DAS181), inhibitors of the influenza RNA polymerase (T-705), antibodies against HA, and antisense strategies, which require further study. 48 …”

Section: Shikimic and Aminoshikimic Acids In Pharmaceutical Chemistrymentioning

confidence: 99%

Current perspectives on applications of shikimic and aminoshikimic acids in pharmaceutical chemistry

Quiroz¹,

Carmona²,

Bolívar³

et al. 2014

RRMC

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Aromatic metabolism comprises the shikimic acid (SA) and the aminoshikimic acid (ASA) pathways. The SA pathway is the common route for the biosynthesis of aromatic amino acids and other metabolites in bacteria, higher plants, fungi, and Apicomplexa parasites, but this pathway is absent in mammals. A variant of the SA pathway known as the ASA pathway branches off from the normal pathway in some bacteria, and its final product, 3-amino-5-hydroxybenzoic acid, is the precursor for many aminoglycoside antibiotics such as kanamycin, neomycin, butirosin, and spectinomycin. The SA pathway includes the key intermediate SA, which is the precursor for the chemical synthesis of the drug oseltamivir phosphate, known commercially as Tamiflu ® , an efficient inhibitor of the neuraminidase enzyme of the seasonal influenza viruses types A and B, avian influenza virus H5N1, and human influenza virus H1N1. Meanwhile, the intermediate of the ASA pathway, ASA, is an attractive candidate for use as the core scaffold for the synthesis of combinatorial libraries and is a potential alternative to SA as a precursor for oseltamivir phosphate synthesis. In this review, we discuss the relevance of the key intermediates SA and ASA as scaffold molecules for the synthesis of diverse chemicals. We highlight the current and potential pharmaceutical applications of these molecules and discuss the main strategies for the production of these aromatic compounds from natural sources and the application of metabolic engineering strategies in diverse bacterial strains for production through biotechnological processes.

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Newer influenza antivirals, biotherapeutics and combinations

Cited by 61 publications

References 175 publications

Preclinical Activity of VX-787, a First-in-Class, Orally Bioavailable Inhibitor of the Influenza Virus Polymerase PB2 Subunit

Preclinical Activity of VX-787, a First-in-Class, Orally Bioavailable Inhibitor of the Influenza Virus Polymerase PB2 Subunit

Akt Inhibitor MK2206 Prevents Influenza pH1N1 Virus Infection In Vitro

Current perspectives on applications of shikimic and aminoshikimic acids in pharmaceutical chemistry

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