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

Rey-Carrizo, Matías; Barniol‐Xicota, Marta; Ma, Chunlong; Frigolé-Vivas, Marta; Torres, Eva; Naesens, Lieve; Llabrés, Salomé; Juárez-Jiménez, Jordi; Luque, F. Javier; DeGrado, William F.; Lamb, Robert A.; Pinto, Lawrence H.; Vázquez, Santiago

doi:10.1021/jm5005804

Cited by 54 publications

(64 citation statements)

References 42 publications

(135 reference statements)

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“…However, it lacks inhibition of the S31N mutant, which is now with more than 95% the predominant form in the transmissible amantadine-resistant H1N1, H3N2, and H5N1 strains. A very similar selectivity profile was found for a series of polycyclic pyrrolidines, such as compounds (28) and (29) [31].…”

Section: M2 Inhibitorssupporting

confidence: 68%

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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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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Section: M2 Inhibitorssupporting

confidence: 68%

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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“…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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“…Aside from the spiro series of compounds, several polycyclic amines also inhibit the V27A and L26F mutants (Table ) . 3‐Azatetracyclo[5.2.1.1 5,8 .0 1,5 ]undecane derivatives ( 33 – 37 ) were found to have potent inhibition against the V27A mutant .…”

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

Cited by 54 publications

References 42 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

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

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

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