Computational and experimental analysis of drug binding to the Influenza M2 channel

Alhadeff, Raphael; Assa, Dror; Astrahan, Peleg; Krugliak, Miriam; Arkin, Isaiah T.

doi:10.1016/j.bbamem.2013.07.033

Cited by 25 publications

(51 citation statements)

References 33 publications

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“…In the negative assay Vpu was expressed at various levels in Escherichia coli . As we have shown previously with the M2 channel from Influenza [34] , [36] , [37] , increased expression of a channel in bacteria results in substantial growth retardation. The extent of growth inhibition can easily be controlled by the amount of inducer ( Fig.…”

Section: Discussionsupporting

confidence: 65%

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Bacteria-Based Analysis of HIV-1 Vpu Channel Activity

et al. 2014

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HIV-1 Vpu is a small, single-span membrane protein with two attributed functions that increase the virus' pathogenicity: degradation of CD4 and inactivation of BST-2. Vpu has also been shown to posses ion channel activity, yet no correlation has been found between this attribute and Vpu's role in viral release. In order to gain further insight into the channel activity of Vpu we devised two bacteria-based assays that can examine this function in detail. In the first assay Vpu was over-expressed, such that it was deleterious to bacterial growth due to membrane permeabilization. In the second and more sensitive assay, the channel was expressed at low levels in K+ transport deficient bacteria. Consequently, Vpu expression enabled the bacteria to grow at otherwise non permissive low K+ concentrations. Hence, Vpu had the opposite impact on bacterial growth in the two assays: detrimental in the former and beneficial in the latter. Furthermore, we show that channel blockers also behave reciprocally in the two assays, promoting growth in the first assay and hindering it in the second assay. Taken together, we investigated Vpu's channel activity in a rapid and quantitative approach that is amenable to high-throughput screening, in search of novel blockers.

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Section: Discussionsupporting

confidence: 65%

“…The first bacteria-based assay that we used was previously tested by us on the Influenza M2 H + channel [34] , [36] , [37] . In this assay the protein is expressed in bacteria at relatively high levels, resulting in growth retardation due to membrane permeabilization.…”

Section: Resultsmentioning

confidence: 99%

Bacteria-Based Analysis of HIV-1 Vpu Channel Activity

et al. 2014

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“…6,15,[26][27][28][29][30][31][32][33] Computer-based binding analyses of several structurally similar potential M2 inhibitors have been rare, however. Eleftheratos et al 16 investigated the binding properties of a series of aminoadamantane compounds by docking calculations.…”

Section: Introductionmentioning

confidence: 99%

Interpreting Thermodynamic Profiles of Aminoadamantane Compounds Inhibiting the M2 Proton Channel of Influenza A by Free Energy Calculations

Homeyer

Ioannidis

Kolarov

et al. 2016

J. Chem. Inf. Model.

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The development of novel anti-influenza drugs is of great importance because of the capability of influenza viruses to occasionally cross interspecies barriers and to rapidly mutate. One class of anti-influenza agents, aminoadamantanes, including the drugs amantadine and rimantadine now widely abandoned due to virus resistance, bind to and block the pore of the transmembrane domain of the M2 proton channel (M2TM) of influenza A. Here, we present one of the still rare studies that interprets thermodynamic profiles from isothermal titration calorimetry (ITC) experiments in terms of individual energy contributions to binding, calculated by the computationally inexpensive implicit solvent/implicit membrane molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approach, for aminoadamantane compounds binding to M2TM of the avian "Weybridge" strain. For all eight pairs of aminoadamantane compounds considered, the trend of the predicted relative binding free energies and their individual components, effective binding energies and changes in the configurational entropy, agrees with experimental measures (ΔΔG, ΔΔH, TΔΔS) in 88, 88, and 50% of the cases. In addition, information yielded by the MM-PBSA approach about determinants of binding goes beyond that available in component quantities (ΔH, ΔS) from ITC measurements. We demonstrate how one can make use of such information to link thermodynamic profiles from ITC with structural causes on the ligand side and, ultimately, to guide decision making in lead optimization in a prospective manner, which results in an aminoadamantane derivative with improved binding affinity against M2TM(Weybridge).

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“…Similar concepts were also applied to bacteria growth assays . When applied to compound screening, two amantadine analogs were found to rescue the growth of bacteria that express the S31N mutant of M2 from the swine influenza strain . These lead compounds might be interesting candidates for further optimization if their mechanism of action is confirmed in electrophysiological assays and antiviral assays.…”

Section: Introductionmentioning

confidence: 99%

“…Several compounds were identified and further confirmed in subsequent TEVC assays and antiviral plaque reduction assays. Similar concepts were also applied to bacteria growth assays . When applied to compound screening, two amantadine analogs were found to rescue the growth of bacteria that express the S31N mutant of M2 from the swine influenza strain .…”

Section: Introductionmentioning

confidence: 99%

Recent progress in designing inhibitors that target the drug‐resistant M2 proton channels from the influenza A viruses

Wang

2015

Biopolymers

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Influenza viruses are the causative agents for seasonal influenza, which results in thousands of deaths and millions of hospitalizations each year. Moreover, sporadic transmission of avian or swan influenza viruses to humans often leads to an influenza pandemic, as there is no preimmunity in the human body to fight against such novel strains. The metastable genome of the influenza viruses, coupled with the reassortment of different strains from a wide range of host origins, leads to the continuous evolution of the influenza virus diversity. Such characteristics of influenza viruses present a grand challenge in devising therapeutic strategies to combat influenza virus infection. This review summarizes recent progress in designing small molecule inhibitors that target the drug-resistant influenza A virus M2 proton channels and highlights the contribution of mechanistic studies of proton conductance to drug discovery. The lessons learned throughout the course of M2 drug discovery might provide insights for designing inhibitors that target other therapeutically important ion channels.

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Computational and experimental analysis of drug binding to the Influenza M2 channel

Cited by 25 publications

References 33 publications

Bacteria-Based Analysis of HIV-1 Vpu Channel Activity

Bacteria-Based Analysis of HIV-1 Vpu Channel Activity

Interpreting Thermodynamic Profiles of Aminoadamantane Compounds Inhibiting the M2 Proton Channel of Influenza A by Free Energy Calculations

Recent progress in designing inhibitors that target the drug‐resistant M2 proton channels from the influenza A viruses

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