3-Azatetracyclo[5.2.1.1<sup>5,8</sup>.0<sup>1,5</sup>]undecane Derivatives: From Wild-Type Inhibitors of the M2 Ion Channel of Influenza A Virus to Derivatives with Potent Activity against the V27A Mutant

Rey-Carrizo, Matías; Torres, Eva; Ma, Chunlong; Barniol‐Xicota, Marta; Wang, Junyang; Wu, Yibing; Naesens, Lieve; DeGrado, William F.; Lamb, Robert A.; Pinto, Lawrence H.; Vázquez, Santiago

doi:10.1021/jm401340p

Cited by 46 publications

(61 citation statements)

References 40 publications

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“…The majority of novel inhibitors identified to date involve either derivatization of amantadine or another M2-inhibitory compound, BL-1743, which was identified from a yeast-based M2 screen (Duque et al, 2011;Kurtz et al, 1995;Rey-Carrizo et al, 2013, 2014Tu et al, 1996;Wang et al, 2009Wang et al, , 2011aWang et al, , b, 2013aWu et al, 2014). Effective inhibitors of several drug-resistant variants have been identified by this approach, although far fewer hits capable of blocking Asn31 channels have arisen.…”

Section: Iav M2mentioning

confidence: 99%

Viroporins: structure, function and potential as antiviral targets

Scott

Griffin

2015

Journal of General Virology

123

146

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The channel-forming activity of a family of small, hydrophobic integral membrane proteins termed 'viroporins' is essential to the life cycles of an increasingly diverse range of RNA and DNA viruses, generating significant interest in targeting these proteins for antiviral development. Viroporins vary greatly in terms of their atomic structure and can perform multiple functions during the virus life cycle, including those distinct from their role as oligomeric membrane channels. Recent progress has seen an explosion in both the identification and understanding of many such proteins encoded by highly significant pathogens, yet the prototypic M2 proton channel of influenza A virus remains the only example of a viroporin with provenance as an antiviral drug target. This review attempts to summarize our current understanding of the channel-forming functions for key members of this growing family, including recent progress in structural studies and drug discovery research, as well as novel insights into the life cycles of many viruses revealed by a requirement for viroporin activity. Ultimately, given the successes of drugs targeting ion channels in other areas of medicine, unlocking the therapeutic potential of viroporins represents a valuable goal for many of the most significant viral challenges to human and animal health.

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Section: Iav M2mentioning

confidence: 99%

Viroporins: structure, function and potential as antiviral targets

Scott

Griffin

2015

Journal of General Virology

123

146

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“…6,11,15 For this reason, in this work we have not synthesized alkylated derivatives of the novel secondary amines herein reported.…”

Section: Chemistrymentioning

confidence: 99%

Easily Accessible Polycyclic Amines that Inhibit the Wild-Type and Amantadine-Resistant Mutants of the M2 Channel of Influenza A Virus

Rey-Carrizo

Barniol‐Xicota

et al. 2014

J. Med. Chem.

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Amantadine inhibits the M2 proton channel of influenza A virus, yet most of the currently circulating strains of the virus carry mutations in the M2 protein that render the virus amantadine-resistant. While most of the research on novel amantadine analogues has revolved around the synthesis of novel adamantane derivatives, we have recently found that other polycyclic scaffolds effectively block the M2 proton channel, including amantadine-resistant mutant channels. In this work, we have synthesized and characterized a series of pyrrolidine derivatives designed as analogues of amantadine. Inhibition of the wild-type M2 channel and the A/M2-S31N, A/M2-V27A, and A/M2-L26F mutant forms of the channel were measured in Xenopus oocytes using two-electrode voltage clamp assays. Most of the novel compounds inhibited the wild-type ion channel in the low micromolar range. Of note, two of the compounds inhibited the amantadine-resistant A/M2-V27A and A/M2-L26F mutant ion channels with submicromolar and low micromolar IC50, respectively. None of the compounds was found to inhibit the S31N mutant ion channel.

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“…Among this limited number of mutants, V27A was shown to be the predominant mutation under drug selection pressure (Furuse et al, 2009a; Furuse et al, 2009b). We therefore are interested in designing the second generation of M2 channel blockers by targeting the V27A mutant (Balannik et al, 2009; Rey-Carrizo et al, 2013; Wang et al, 2011a; Wang et al, 2011b). …”

Section: Introductionmentioning

confidence: 99%

“…Although a few compounds were reported to inhibit the M2-V27A mutant channel (Rey-Carrizo et al, 2014; Rey-Carrizo et al, 2013; Wang et al, 2011a), there has been no report on their antiviral activity against the M2-V27A-containing influenza A virus. Given the promising channel blockage efficacy of compound 3 in inhibiting both the M2-WT and the M2-V27A mutant, we took a step further to evaluate the in vitro and in vivo antiviral efficacy of compound 3 .…”

Section: Introductionmentioning

confidence: 99%

An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses

Musharrafieh

et al. 2017

Antiviral Research

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Adamantanes such as amantadine (1) and rimantadine (2) are FDA-approved anti-influenza drugs that act by inhibiting the wild-type M2 proton channel from influenza A viruses, thereby inhibiting the uncoating of the virus. Although adamantanes have been successfully used for more than four decades, their efficacy was curtailed by emerging drug resistance. Among the limited number of M2 mutants that confer amantadine resistance, the M2-V27A mutant was found to be the predominant mutant under drug selection pressure, thereby representing a high profile antiviral drug target. Guided by molecular dynamics simulations, we previously designed first-in-class M2-V27A inhibitors. One of the potent lead compounds, spiroadamantane amine (3), inhibits both the M2-WT and M2-V27A mutant with IC50 values of 18.7 and 0.3 μM, respectively, in in vitro electrophysiological assays. Encouraged by these findings, in this study we further examine the in vitro and in vivo antiviral activity of compound 3 in inhibiting both amantadine-sensitive and -resistant influenza A viruses. Compound 3 not only had single to submicromolar EC50 values against M2-WT- and M2-V27A-containing influenza A viruses in antiviral assays, but also rescued mice from lethal viral infection by either M2-WT- or M2-V27A-containing influenza A viruses. In addition, we report the design of two analogs of compound 3, and one was found to have improved in vitro antiviral activity over compound 3. Collectively, this study represents the first report demonstrating the in vivo antiviral efficacy of inhibitors targeting M2 mutants. The results suggest that inhibitors targeting drug-resistant M2 mutants are promising antiviral drug candidates worthy of further development.

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3-Azatetracyclo[5.2.1.1^5,8.0^1,5]undecane Derivatives: From Wild-Type Inhibitors of the M2 Ion Channel of Influenza A Virus to Derivatives with Potent Activity against the V27A Mutant

Cited by 46 publications

References 40 publications

Viroporins: structure, function and potential as antiviral targets

Viroporins: structure, function and potential as antiviral targets

Easily Accessible Polycyclic Amines that Inhibit the Wild-Type and Amantadine-Resistant Mutants of the M2 Channel of Influenza A Virus

An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses

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3-Azatetracyclo[5.2.1.15,8.01,5]undecane Derivatives: From Wild-Type Inhibitors of the M2 Ion Channel of Influenza A Virus to Derivatives with Potent Activity against the V27A Mutant

Cited by 46 publications

References 40 publications

Viroporins: structure, function and potential as antiviral targets

Viroporins: structure, function and potential as antiviral targets

Easily Accessible Polycyclic Amines that Inhibit the Wild-Type and Amantadine-Resistant Mutants of the M2 Channel of Influenza A Virus

An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses

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Product

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3-Azatetracyclo[5.2.1.1^5,8.0^1,5]undecane Derivatives: From Wild-Type Inhibitors of the M2 Ion Channel of Influenza A Virus to Derivatives with Potent Activity against the V27A Mutant