Identification of camphor derivatives as novel M2 ion channel inhibitors of influenza A virus

Zhao, Xin; Zhang, Zhenwei; Cui, Wei; Zhou, Yang; Dong, Jianghong; Jie, Yanling; Wan, Junting; Xu, Yong; Hu, Wenhui

doi:10.1039/c4md00515e

Cited by 21 publications

(7 citation statements)

References 36 publications

(41 reference statements)

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“… a Virus strain, A/Guangzhou/GIRD/07/2009 (H1N1). b All the compounds were also tested for the inhibitory effect against A/WSN/33 and A/HK/68 strains based on a CCK-8 reagent measurement method 44 . Compounds 6, 7, 10, 11–18, 23, 24, 26, 28, 30, 36 and 40 exhibited range of micromolar to sub-micromolar activity against both strains (the data were not shown), consistent with this experiment with the Guangzhou strain, compound 18 ( M090 ) was the most potent inhibitor of the WSN and HK strains too. c MCC: minimum cytotoxic concentration, or concentration which led to minimal change in cell morphology after 48 h incubation with compound. d “−” represent that no viral inhibition occurs when the concentrations of compounds were lower than MCC. …”

Section: Figurementioning

confidence: 99%

“… b All the compounds were also tested for the inhibitory effect against A/WSN/33 and A/HK/68 strains based on a CCK-8 reagent measurement method 44 . Compounds 6, 7, 10, 11–18, 23, 24, 26, 28, 30, 36 and 40 exhibited range of micromolar to sub-micromolar activity against both strains (the data were not shown), consistent with this experiment with the Guangzhou strain, compound 18 ( M090 ) was the most potent inhibitor of the WSN and HK strains too. …”

Section: Figurementioning

confidence: 99%

“… a Virus strain, A/Guangzhou/GIRD/07/2009 (H1N1). b All of the compounds were also tested for the inhibitory effect against A/WSN/33 and A/HK/68 strains based on a CCK-8 reagent measurement method . Compounds 6 , 7 , 10 , 11 – 18 , 23 , 24 , 26 , 28 , 30 , 36 , and 40 exhibited range of micromolar to submicromolar activity against both strains (the data were not shown).…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Highly Potent Pinanamine-Based Inhibitors against Amantadine- and Oseltamivir-Resistant Influenza A Viruses

Zhao

Zhou

et al. 2018

J. Med. Chem.

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Influenza pandemic is a constant major threat to public health caused by influenza A viruses (IAV). IAVs are sub-categorized by the surface proteins: hemagglutinin (HA) and neuraminidase (NA), in which they are both essential targets for drug discovery. While it is of great concern that NA inhibitor oseltamivir resistant strains are frequently identified from human or avian influenza virus, structural and functional characterization of influenza HA has raised hopes for new antiviral therapies. In this study, we explored a structure-activity relationship (SAR) of pinanamine-based antivirals and discovered a potent inhibitor M090 against amantadine-resistant viruses, including the 2009 H1N1 pandemic strains, and oseltamivir- resistant viruses. Mechanism of action studies, particularly hemolysis inhibition, indicated that M090 targets influenza HA and it occupied a highly conserved pocket of the HA2 domain and inhibited virus-mediated membrane fusion by “locking” the bending state of HA2 during the conformational rearrangement process. This work provides new binding sites within the HA protein and indicates that this pocket may be a promising target for broad-spectrum anti-influenza A drug design and development.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discovery of Highly Potent Pinanamine-Based Inhibitors against Amantadine- and Oseltamivir-Resistant Influenza A Viruses

Zhao

Zhou

et al. 2018

J. Med. Chem.

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“…On the other hand, 1,7,7-trimethylbicycloĳ2.2.1]heptan scaffolds are structural units in numerous bioactive compounds such as camphor and borneol that possess different biological activity; for example, antimicrobial, 7 antiviral, [8][9][10] antioxidant, 11 analgesic 12 and receptor antagonist. 13 The structural features of this system such as gem-dimethyl group and conformationally rigid bicycle can modify the rotational barriers and stabilise a bioactive conformation and provide favourable van der Waals interactions with the binding site of the target protein.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antiviral activity of camphor-based 1,3-thiazolidin-4-one and thiazole derivatives as Orthopoxvirus-reproduction inhibitors

et al. 2018

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“…Therefore, while Amt leads to 91.0% inhibition of the proton conductance through the wild-type (wt) M2 channel at 100 μM concentration (IC 50 of 16.0 μM), the inhibition of the V27A channel is only 10.8%, thus revealing a much weaker inhibitory potency. Promising progresses in developing novel drugs targeting these mutated strains have been reported in the past years. − In particular, Wang et al reported spiro analogues of Amt capable of inhibiting the L26F and V27A M2 mutants with good efficacy in electrophysiological and plaque reduction assays. − More recently, a polycyclic pyrrolidine has been reported to be the first nonadamantane inhibitor of the V27A variant. , On the other hand, an isoxazole derivative of Amt has been found to inhibit the S31N variant with a potency that compares with Amt in inhibiting the wt virus strain. , …”

Section: Introductionmentioning

confidence: 99%

Mechanism of the Pseudoirreversible Binding of Amantadine to the M2 Proton Channel

et al. 2016

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The M2 proton channel of influenza A virus is an integral membrane protein involved in the acidification of the viral interior, a step necessary for the release of the viral genetic material and replication of new virions. The aim of this study is to explore the mechanism of drug (un)binding to the M2 channel in order to gain insight into the structural and energetic features relevant for the development of novel inhibitors. To this end, we have investigated the binding of amantadine (Amt) to the wild type (wt) M2 channel and its V27A variant using multiple independent molecular dynamics simulations, exploratory conventional metadynamics, and multiple-walkers well-tempered metadynamics calculations. The results allow us to propose a sequential mechanism for the (un)binding of Amt to the wt M2 channel, which involves the adoption of a transiently populated intermediate (up state) leading to the thermodynamically favored down binding mode in the channel pore. Furthermore, they suggest that chloride anions play a relevant role in stabilizing the down binding mode of Amt to the wt channel, giving rise to a kinetic trapping that explains the experimentally observed pseudoirreversible inhibition of the wt channel by Amt. We propose that this trapping mechanism underlies the inhibitory activity of potent M2 channel blockers, as supported by the experimental confirmation of the irreversible binding of a pyrrolidine analogue from electrophysiological current assays. Finally, the results reveal that the thermodynamics and kinetics of Amt (un)binding is very sensitive to the V27A mutation, providing a quantitative rationale to the drastic decrease in inhibitory potency against the V27A variant. Overall, these findings pave the way to explore the inhibitory activity of Amt-related analogues in mutated M2 channel variants, providing guidelines for the design of novel inhibitors against resistant virus strains.

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Identification of camphor derivatives as novel M2 ion channel inhibitors of influenza A virus

Abstract: Amantadine derivatives have been the only drugs marketed as M2 inhibitors of influenza A for decades.

Cited by 21 publications

References 36 publications

Discovery of Highly Potent Pinanamine-Based Inhibitors against Amantadine- and Oseltamivir-Resistant Influenza A Viruses

Discovery of Highly Potent Pinanamine-Based Inhibitors against Amantadine- and Oseltamivir-Resistant Influenza A Viruses

Synthesis and antiviral activity of camphor-based 1,3-thiazolidin-4-one and thiazole derivatives as Orthopoxvirus-reproduction inhibitors

Mechanism of the Pseudoirreversible Binding of Amantadine to the M2 Proton Channel

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