Synthesis and inhibitory effects of novel pyrimido-pyrrolo-quinoxalinedione analogues targeting nucleoproteins of influenza A virus H1N1

Lin, Meng I.; Su, Bo; Lee, Chia Hsin; Wang, Suz Ting; Wu, Wen; Dangate, Prasad S.; Wang, Shi Yun; Huang, Wen I.; Cheng, Ting-Jen Rachel; Lin, Olivia A.; Cheng, Yih Shyun E.; Tseng, Yufeng J.; Sun, Chung‐Ming

doi:10.1016/j.ejmech.2015.08.016

Cited by 25 publications

(24 citation statements)

References 28 publications

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“…(C) Predicted binding sites for compound 4, naproxen and naproxen C0, RK424, and F66 . (D) Binding site for nucleozin (proven by cocrystallization) and that predicted for PPQ‐581 . The overlap of the nucleozin‐binding site with that of compound 4 or PPQ‐581 is colored in maroon and orange, respectively.…”

Section: Strategies To Interfere With the Influenza Virus Polymerasementioning

confidence: 99%

See 1 more Smart Citation

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

Stevaert

Naesens

2016

Medicinal Research Reviews

136

151

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Influenza viruses cause seasonal epidemics and pandemic outbreaks associated with significant morbidity and mortality, and a huge cost. Since resistance to the existing anti‐influenza drugs is rising, innovative inhibitors with a different mode of action are urgently needed. The influenza polymerase complex is widely recognized as a key drug target, given its critical role in virus replication and high degree of conservation among influenza A (of human or zoonotic origin) and B viruses. We here review the major progress that has been made in recent years in unravelling the structure and functions of this protein complex, enabling structure‐aided drug design toward the core regions of the PA endonuclease, PB1 polymerase, or cap‐binding PB2 subunit. Alternatively, inhibitors may target a protein–protein interaction site, a cellular factor involved in viral RNA synthesis, the viral RNA itself, or the nucleoprotein component of the viral ribonucleoprotein. The latest advances made for these diverse pharmacological targets have yielded agents in advanced (i.e., favipiravir and VX‐787) or early clinical testing, besides several experimental inhibitors in various stages of development, which are all covered here.

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Section: Strategies To Interfere With the Influenza Virus Polymerasementioning

confidence: 99%

“…Another NP‐aggregating compound, PPQ‐581 , shows no cross‐resistance to nucleozin and selects for a resistance mutation adjacent to the nucleozin‐binding site (Fig. D) …”

Section: Strategies To Interfere With the Influenza Virus Polymerasementioning

confidence: 99%

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

Stevaert

Naesens

2016

Medicinal Research Reviews

136

151

View full text Add to dashboard Cite

show abstract

“…6A). The EC 50 value of PPQ581 against the A/WNS/33 (H1N1) strain was 2.3 μM [108]. Subsequent mechanistic studies revealed that PPQ581 similarly imparted the vRNP nuclear trafficking as that of nucleozin, suggesting that both compounds might exert their antiviral activity through the same target: the NP protein.…”

Section: Inhibitors Targeting Influenza a Virus Npmentioning

confidence: 99%

Section: Fig (1)mentioning

confidence: 99%

Influenza A Virus Nucleoprotein: A Highly Conserved Multi-Functional Viral Protein as a Hot Antiviral Drug Target

Sneyd

Dekant

et al. 2017

CTMC

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Prevention and treatment of influenza virus infection is an ongoing unmet medical need. Each year, thousands of deaths and millions of hospitalizations are attributed to influenza virus infection, which poses a tremendous health and economic burden to the society. Aside from the annual influenza season, influenza viruses also lead to occasional influenza pandemics as a result of emerging or re-emerging influenza strains. Influenza viruses are RNA viruses that exist in quasispecies, meaning that they have a very diverse genetic background. Such a feature creates a grand challenge in devising therapeutic intervention strategies to inhibit influenza virus replication, as a single agent might not be able to inhibit all influenza virus strains. Both classes of currently approved anti-influenza drugs have limitations: the M2 channel blockers amantadine and rimantadine are no longer recommended for use in the U.S. due to predominant drug resistance, and resistance to the neuraminidase inhibitor oseltamivir is continuously on the rise. In pursuing the next generation of antiviral drugs with broad-spectrum activity and higher genetic barrier of drug resistance, the influenza virus nucleoprotein (NP) stands out as a high-profile drug target. This review summarizes recent developments in designing inhibitors targeting influenza NP and their mechanisms of action.

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“…Similarly, Verdinixor, a representative of a new class of CRM1 inhibitor, forms a reversible covalent bond with C258 of CRM1 and thereby inhibits replications of influenza A subtypes H1N1, H5N1, and H7N9 (Perwitasari et al, 2014). Inhibition of vRNP nuclear export by an inhibitor with an unknown target, 14-deoxy-11,12-dehydroandrographolide (Cai et al, 2015), or NP-target inhibitors such as pyrimido-pyrrolo-quinoxalinedione analog (Lin et al, 2015) and 1,3,4,6-tetra-O-galloyl-β-D-glucopyranoside (Chang et al, 2016) can also potentially diminish replication of influenza viruses. Moreover, targeting of the third NES domain of NP (NP-NES3) by an inhibitor we discovered, RK424, results in antiviral effects in vitro and in vivo (Kakisaka et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of CRM1-mediated nuclear export of influenza A nucleoprotein and nuclear export protein as a novel target for antiviral drug development

et al. 2017

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An anti-influenza compound, DP2392-E10 based on inhibition of the nuclear export function of the viral nucleoprotein-nuclear export signal 3 (NP-NES3) domain was successfully identified by our previous high-throughput screening system. Here, we demonstrated that DP2392-E10 exerts its antiviral effect by inhibiting replication of a broad range of influenza A subtypes. In regard to the molecular mechanism, we revealed that DP2392-E10 inhibits nuclear export of both viral NP and nuclear export protein (NEP). More specifically, in vitro pull-down assays revealed that DP2392-E10 directly binds cellular CRM1, which mediates nuclear export of NP and NEP. In silico docking suggested that DP2392-E10 binds at a region close to the HEAT9 and HEAT10 domains of CRM1. Together, these results indicate that the CRM1-mediated nuclear export function of influenza virus represents a new potential target for antiviral drug development, and also provide a core structure for a novel class of inhibitors that target this function.

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Synthesis and inhibitory effects of novel pyrimido-pyrrolo-quinoxalinedione analogues targeting nucleoproteins of influenza A virus H1N1

Cited by 25 publications

References 28 publications

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

Influenza A Virus Nucleoprotein: A Highly Conserved Multi-Functional Viral Protein as a Hot Antiviral Drug Target

Inhibition of CRM1-mediated nuclear export of influenza A nucleoprotein and nuclear export protein as a novel target for antiviral drug development

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