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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

[Image: see text] 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...

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Autores principales: Rey-Carrizo, Matias, Barniol-Xicota, Marta, Ma, Chunlong, Frigolé-Vivas, Marta, Torres, Eva, Naesens, Lieve, Llabrés, Salomé, Juárez-Jiménez, Jordi, Luque, Francisco J., DeGrado, William F., Lamb, Robert A., Pinto, Lawrence H., Vázquez, Santiago
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096222/
https://www.ncbi.nlm.nih.gov/pubmed/24941437
http://dx.doi.org/10.1021/jm5005804
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author Rey-Carrizo, Matias
Barniol-Xicota, Marta
Ma, Chunlong
Frigolé-Vivas, Marta
Torres, Eva
Naesens, Lieve
Llabrés, Salomé
Juárez-Jiménez, Jordi
Luque, Francisco J.
DeGrado, William F.
Lamb, Robert A.
Pinto, Lawrence H.
Vázquez, Santiago
author_facet Rey-Carrizo, Matias
Barniol-Xicota, Marta
Ma, Chunlong
Frigolé-Vivas, Marta
Torres, Eva
Naesens, Lieve
Llabrés, Salomé
Juárez-Jiménez, Jordi
Luque, Francisco J.
DeGrado, William F.
Lamb, Robert A.
Pinto, Lawrence H.
Vázquez, Santiago
author_sort Rey-Carrizo, Matias
collection PubMed
description [Image: see text] 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 IC(50), respectively. None of the compounds was found to inhibit the S31N mutant ion channel.
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spelling pubmed-40962222015-06-18 Easily Accessible Polycyclic Amines that Inhibit the Wild-Type and Amantadine-Resistant Mutants of the M2 Channel of Influenza A Virus Rey-Carrizo, Matias Barniol-Xicota, Marta Ma, Chunlong Frigolé-Vivas, Marta Torres, Eva Naesens, Lieve Llabrés, Salomé Juárez-Jiménez, Jordi Luque, Francisco J. DeGrado, William F. Lamb, Robert A. Pinto, Lawrence H. Vázquez, Santiago J Med Chem [Image: see text] 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 IC(50), respectively. None of the compounds was found to inhibit the S31N mutant ion channel. American Chemical Society 2014-06-18 2014-07-10 /pmc/articles/PMC4096222/ /pubmed/24941437 http://dx.doi.org/10.1021/jm5005804 Text en Copyright © 2014 American Chemical Society Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html)
spellingShingle Rey-Carrizo, Matias
Barniol-Xicota, Marta
Ma, Chunlong
Frigolé-Vivas, Marta
Torres, Eva
Naesens, Lieve
Llabrés, Salomé
Juárez-Jiménez, Jordi
Luque, Francisco J.
DeGrado, William F.
Lamb, Robert A.
Pinto, Lawrence H.
Vázquez, Santiago
Easily Accessible Polycyclic Amines that Inhibit the Wild-Type and Amantadine-Resistant Mutants of the M2 Channel of Influenza A Virus
title Easily Accessible Polycyclic Amines that Inhibit the Wild-Type and Amantadine-Resistant Mutants of the M2 Channel of Influenza A Virus
title_full Easily Accessible Polycyclic Amines that Inhibit the Wild-Type and Amantadine-Resistant Mutants of the M2 Channel of Influenza A Virus
title_fullStr Easily Accessible Polycyclic Amines that Inhibit the Wild-Type and Amantadine-Resistant Mutants of the M2 Channel of Influenza A Virus
title_full_unstemmed Easily Accessible Polycyclic Amines that Inhibit the Wild-Type and Amantadine-Resistant Mutants of the M2 Channel of Influenza A Virus
title_short Easily Accessible Polycyclic Amines that Inhibit the Wild-Type and Amantadine-Resistant Mutants of the M2 Channel of Influenza A Virus
title_sort easily accessible polycyclic amines that inhibit the wild-type and amantadine-resistant mutants of the m2 channel of influenza a virus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096222/
https://www.ncbi.nlm.nih.gov/pubmed/24941437
http://dx.doi.org/10.1021/jm5005804
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