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.
We have synthesized and characterized a series of compounds containing the 3-azatetracyclo[5.2.1.1(5,8).0(1,5)]undecane scaffold designed as analogues of amantadine, an inhibitor of the M2 proton channel of influenza A virus. Inhibition of the wild-type (WT) M2 channel and the amantadine-resistant A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Most of the novel compounds inhibited the WT ion channel in the low micromolar range. Of note, several compounds inhibited the A/M2 V27A mutant ion channel, one of them with submicromolar IC50. None of the compounds was found to inhibit the S31N mutant ion channel. The antiviral activity of three novel dual WT and A/M2-V27A channels inhibitors was confirmed by influenza virus yield assays.
Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona , Av. Joan XXIII s/n, Barcelona E-08028, Spain.
Matias
M
Rey-Carrizo
Eva
E
Torres
Chunlong
C
Ma
Marta
M
Barniol-Xicota
Jun
J
Wang
Yibing
Y
Wu
Lieve
L
Naesens
William F
WF
DeGrado
Robert A
RA
Lamb
Lawrence H
LH
Pinto
Santiago
S
Vázquez
D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001372:Aza Compounds / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D001952:Bridged-Ring Compounds / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D004285:Dogs; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects; D006146:Guanidines / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000235:genetics; D020128:Inhibitory Concentration 50; D061985:Madin Darby Canine Kidney Cells; D009154:Mutation; D011759:Pyrrolidines / Q000737:chemistry; D013329:Structure-Activity Relationship; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D000086082:Viroporin Proteins
D000547:Amantadine; D000998:Antiviral Agents; D001372:Aza Compounds; D001952:Bridged-Ring Compounds; D006146:Guanidines; D011759:Pyrrolidines; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins; C032519:pyrrolidine