Title: Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus
Authors: Duque, MD ×
Ma, C
Torres, E
Wang, J
Naesens, Lieve
Juarez-Jiménez, J
Camps, P
Luque, FJ
DeGrado, WF
Lamb, RA
Pinto, LH
Vazquez, S #
Issue Date: Apr-2011
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:54 issue:8 pages:2646-2657
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.
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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