Potential Targets and Their Relevant Inhibitors in Anti-influenza Fields

Gong, Jianzhi; Fang, Hao; Li, Minyong; Liu, Yu; Yang, Kai-Cheng; Liu, Yingzi; Xu, Wenfang

doi:10.2174/092986709789104984

Cited by 36 publications

(37 citation statements)

References 251 publications

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“…New anti-influenza drugs are needed due to the limitations of approved agents, primarily, the variable emergence of neuraminidase inhibitor resistance and the limited time window after infection (48 h) within which these agents are active (44,45).…”

Section: Discussionmentioning

confidence: 99%

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

169

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: 99%

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

169

189

View full text Add to dashboard Cite

show abstract

“…More surprisingly, the new 2009 H1N1 virus, also called S-OIV (Swine-Originated Influenza Virus), was susceptible to Oseltamivir initially (12), but developed Oseltamivirresistant variants in 4 mo (13). In addition to the neuraminidase and the M2, influenza polymerase has been considered as a promising antiinfluenza drug target because its mode of action is very different from the human RNA polymerases (14,15).…”

mentioning

confidence: 99%

High-throughput identification of compounds targeting influenza RNA-dependent RNA polymerase activity

Cheng

Lin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

120

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As influenza viruses have developed resistance towards current drugs, new inhibitors that prevent viral replication through different inhibitory mechanisms are useful. In this study, we developed a screening procedure to search for new antiinfluenza inhibitors from 1,200,000 compounds and identified previously reported as well as new antiinfluenza compounds. Several antiinfluenza compounds were inhibitory to the influenza RNA-dependent RNA polymerase (RdRP), including nucleozin and its analogs. The most potent nucleozin analog, 3061 (FA-2), inhibited the replication of the influenza A/WSN/33 (H1N1) virus in MDCK cells at submicromolar concentrations and protected the lethal H1N1 infection of mice. Influenza variants resistant to 3061 (FA-2) were isolated and shown to have the mutation on nucleoprotein (NP) that is distinct from the recently reported resistant mutation of Y289H [Kao R, et al. (2010) Nat Biotechnol 28:600]. Recombinant influenza carrying the Y52H NP is also resistant to 3061 (FA-2), and NP aggregation induced by 3061 (FA-2) was identified as the most likely cause for inhibition. In addition, we identified another antiinfluenza RdRP inhibitor 367 which targets PB1 protein but not NP. A mutant resistant to 367 has H456P mutation at the PB1 protein and both the recombinant influenza and the RdRP expressing the PB1 H456P mutation have elevated resistance to 367. Our high-throughput screening (HTS) campaign thus resulted in the identification of antiinfluenza compounds targeting RdRP activity.high-throughput screening | antiinfluenza | influenza NP | influenza PB1 | chemical genetics

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“…They can be divided into the serologically different types A, B, and C, whereas infections with the type C in men are usually only associated with minor symptoms and thus not further discussed in this article. The genome of the subtypes A and B consists of eight single negative-stranded RNA segments, which encode for about 12 different proteins [2,3]. The viral envelope is covered on its surface by multiple copies of membrane-integrated glycoprotein spikes consisting of receptor-binding trimeric hemagglutinin (HA), to a lesser extent of the sugar-cleaving homotetrameric neuraminidase (NA) and of a few membrane-spanning proton channel M2 tetramers.…”

Section: Structure and Replication Of Influenza Virusesmentioning

confidence: 99%

“…Especially, the His274Tyr mutant of NA, which was also found among the 2009 pandemic flu and highly pathogenic avian influenza H5N1 virus strains, is much less susceptible to oseltamivir. The sterically more demanding Tyr side chain induces a shift of the residue Glu276, which weakens the affinity to the pentanyl group of oseltamivir (3) and peramivir (4), whereas the analogous glycerol moiety of zanamivir still enables sufficient binding to the displaced Glu276. A few additional active site mutations reduce the efficacy of the NA inhibitors (NAIs); therefore, the development of new and more effective derivatives is ongoing.…”

Section: Structure and Replication Of Influenza Virusesmentioning

confidence: 99%

“…In virus-infected MDCK cells, an IC 50 value of 5.6 μM was determined based on the cytopathic effect. Additional examples of such SA-derived anti-adhesion drugs have been reviewed [3]. However, the synthesis of larger SA conjugates is a relatively laborious task, which might be a clear drawback compared to the straightforward preparation of small-molecule drugs.…”

Section: Anti-adhesion Drugsmentioning

confidence: 99%

See 1 more Smart Citation

Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

Steinmetzer¹,

Hardes²,

Böttcher‐Friebertshäuser³

et al. 2014

Topics in Medicinal Chemistry

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Only four drugs are approved for the specific treatment of acute influenza infections worldwide. These drugs address either the viral neuraminidase or the M2-channel but suffer from poor efficacy and the rapid emergence of drug resistances. Some additional drugs are launched in few countries, but their efficacy is relatively low and often limited to certain influenza strains. Ideally, new drugs should possess a broad potency against all influenza viruses and be less susceptible to the development of resistances. The propagation cycle of the influenza virus offers many possibilities for the development of new anti-influenza drugs. Various compounds addressing viral targets reached clinical development, from which the most-advanced candidate is the polymerase inhibitor favipiravir. A promising strategy could be also the inhibition of host targets and signaling pathways, e.g., by already approved kinase inhibitors, anti-inflammatory drugs, or immunomodulatory agents. However, the benefit of these agents has to be demonstrated in controlled clinical trials. A broader arsenal of approved drugs will offer the possibility for more efficient combinatorial therapies in the future. The first proof of concept studies for such multiple drug therapies in infected mice revealed beneficial effects. Moreover, this strategy should reduce the rapid emergence of resistant influenza strains.

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Potential Targets and Their Relevant Inhibitors in Anti-influenza Fields

Cited by 36 publications

References 251 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

High-throughput identification of compounds targeting influenza RNA-dependent RNA polymerase activity

Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

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