The de-guanidinylated derivative of peramivir remains a potent inhibitor of influenza neuraminidase

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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“…An exception is the deguanidinylated peramivir analogue (20), which retains relatively strong inhibitory potency (K i ¼ 7.5 nM) (Fig. 6) [22].…”

Section: Structure and Replication Of Influenza Virusesmentioning

confidence: 98%

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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“…Many efforts have been made to discover new NA inhibitors with various scaffolds, including aromatic1213, dihydropyrane1415, cyclopentane16, cyclohexene1718, pyrrolidine19 and others20. There are also many natural product compounds reported to have anti-NA activity21.…”

mentioning

confidence: 99%

Potential New H1N1 Neuraminidase Inhibitors from Ferulic Acid and Vanillin: Molecular Modelling, Synthesis and in Vitro Assay

Hariono

Abdullah

Damodaran

et al. 2016

Sci Rep

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We report the computational and experimental efforts in the design and synthesis of novel neuraminidase (NA) inhibitors from ferulic acid and vanillin. Two proposed ferulic acid analogues, MY7 and MY8 were predicted to inhibit H1N1 NA using molecular docking. From these two analogues, we designed, synthesised and evaluated the biological activities of a series of ferulic acid and vanillin derivatives. The enzymatic H1N1 NA inhibition assay showed MY21 (a vanillin derivative) has the lowest IC50 of 50 μM. In contrast, the virus inhibition assay showed MY15, a ferulic acid derivative has the best activity with the EC50 of ~0.95 μM. Modelling studies further suggest that these predicted activities might be due to the interactions with conserved and essential residues of NA with ΔGbind values comparable to those of oseltamivir and zanamivir, the two commercial NA inhibitors.

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“…However, neuraminidase inhibition assays against an inactivated influenza virus showed that 10 had a K i barely into the micromolar range, consistent with a compound that engages with only two of the four subregions of the active site. 26 Nonetheless, full kinetic characterization revealed 10 to be a competitive inhibitor of the enzyme (Figure 3A), suggesting that the compound was accessing the active site as designed.…”

mentioning

confidence: 99%

“…The increase in activity with the installation of the guanidine function provides additional evidence that the bicyclic compounds described here are binding in the expected geometry within the active site. 26 …”

mentioning

confidence: 99%

A Rigid Bicyclic Platform for the Generation of Conformationally Locked Neuraminidase Inhibitors

Brant

Wulff

2012

Org. Lett.

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Rapid mutation of the influenza virus through genetic mixing raises the prospect of new strains that are both highly transmissible and highly lethal, and which have the ability to evade both immunization strategies (through mutation of hemagglutinin) and current therapies (through mutation of neuraminidase). Inspired by a need for next-generation therapeutics, a synthetic strategy for a new class of rigid, bicyclic inhibitors of influenza neuraminidase is reported.

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The de-guanidinylated derivative of peramivir remains a potent inhibitor of influenza neuraminidase

Cited by 18 publications

References 41 publications

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

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

Potential New H1N1 Neuraminidase Inhibitors from Ferulic Acid and Vanillin: Molecular Modelling, Synthesis and in Vitro Assay

A Rigid Bicyclic Platform for the Generation of Conformationally Locked Neuraminidase Inhibitors

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