Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus

María D. Duque, Chunlong Ma, Eva Torres, Jun Wang, Lieve Naesens, Jordi Juárez-Jiménez, Pelayo Camps, F. Javier Luque, William F. Degrado, Robert A. Lamb, Lawrence H. Pinto, Santiago Vázquez

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30, and Ser31, though ring expansion restricts the positioning in the binding site. Only the smallest analogue 8 was found to inhibit the S31N mutant ion channel. The structure-activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.

Original languageEnglish (US)
Pages (from-to)2646-2657
Number of pages12
JournalJournal of Medicinal Chemistry
Volume54
Issue number8
DOIs
StatePublished - Apr 28 2011
Externally publishedYes

Fingerprint

Amantadine
Influenza A virus
Ion Channels
Electrodes
H3N2 Subtype Influenza A Virus
Polycyclic Compounds
Structure-Activity Relationship
Xenopus
Human Influenza
Oocytes
Protons
Binding Sites
Viruses
Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Duque, M. D., Ma, C., Torres, E., Wang, J., Naesens, L., Juárez-Jiménez, J., ... Vázquez, S. (2011). Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus. Journal of Medicinal Chemistry, 54(8), 2646-2657. https://doi.org/10.1021/jm101334y

Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus. / Duque, María D.; Ma, Chunlong; Torres, Eva; Wang, Jun; Naesens, Lieve; Juárez-Jiménez, Jordi; Camps, Pelayo; Luque, F. Javier; Degrado, William F.; Lamb, Robert A.; Pinto, Lawrence H.; Vázquez, Santiago.

In: Journal of Medicinal Chemistry, Vol. 54, No. 8, 28.04.2011, p. 2646-2657.

Research output: Contribution to journalArticle

Duque, MD, Ma, C, Torres, E, Wang, J, Naesens, L, Juárez-Jiménez, J, Camps, P, Luque, FJ, Degrado, WF, Lamb, RA, Pinto, LH & Vázquez, S 2011, 'Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus', Journal of Medicinal Chemistry, vol. 54, no. 8, pp. 2646-2657. https://doi.org/10.1021/jm101334y
Duque, María D. ; Ma, Chunlong ; Torres, Eva ; Wang, Jun ; Naesens, Lieve ; Juárez-Jiménez, Jordi ; Camps, Pelayo ; Luque, F. Javier ; Degrado, William F. ; Lamb, Robert A. ; Pinto, Lawrence H. ; Vázquez, Santiago. / Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 8. pp. 2646-2657.
@article{a13105c0bc7e45d18cb3d40cc80ad423,
title = "Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus",
abstract = "Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30, and Ser31, though ring expansion restricts the positioning in the binding site. Only the smallest analogue 8 was found to inhibit the S31N mutant ion channel. The structure-activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.",
author = "Duque, {Mar{\'i}a D.} and Chunlong Ma and Eva Torres and Jun Wang and Lieve Naesens and Jordi Ju{\'a}rez-Jim{\'e}nez and Pelayo Camps and Luque, {F. Javier} and Degrado, {William F.} and Lamb, {Robert A.} and Pinto, {Lawrence H.} and Santiago V{\'a}zquez",
year = "2011",
month = "4",
day = "28",
doi = "10.1021/jm101334y",
language = "English (US)",
volume = "54",
pages = "2646--2657",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "8",

}

TY - JOUR

T1 - Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus

AU - Duque, María D.

AU - Ma, Chunlong

AU - Torres, Eva

AU - Wang, Jun

AU - Naesens, Lieve

AU - Juárez-Jiménez, Jordi

AU - Camps, Pelayo

AU - Luque, F. Javier

AU - Degrado, William F.

AU - Lamb, Robert A.

AU - Pinto, Lawrence H.

AU - Vázquez, Santiago

PY - 2011/4/28

Y1 - 2011/4/28

N2 - Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30, and Ser31, though ring expansion restricts the positioning in the binding site. Only the smallest analogue 8 was found to inhibit the S31N mutant ion channel. The structure-activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.

AB - Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30, and Ser31, though ring expansion restricts the positioning in the binding site. Only the smallest analogue 8 was found to inhibit the S31N mutant ion channel. The structure-activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.

UR - http://www.scopus.com/inward/record.url?scp=79955451255&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79955451255&partnerID=8YFLogxK

U2 - 10.1021/jm101334y

DO - 10.1021/jm101334y

M3 - Article

VL - 54

SP - 2646

EP - 2657

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 8

ER -