title: Amiloride derivatives block ion channel activity and enhancement of virus-like particle budding caused by HIV-1 protein Vpu.
abstract: The Vpu protein of human immunodeficiency virus type 1 forms cation-selective ion channels and enhances the process of virion budding and release. Mutagenesis studies have shown that the N-terminal transmembrane domain primarily controls both of these activities. Here we report that the Vpu ion channel is inhibited by the amiloride derivatives 5-(N,N-hexamethylene)amiloride and 5-(N,N-dimethyl)amiloride but not by amiloride itself, nor by amantadine. Hexamethyleneamiloride also inhibits budding of virus-like particles from HeLa cells expressing HIV-1 Gag and Vpu proteins. These results confirm the link between Vpu ion channel activity and the budding process and also suggest that amiloride derivatives might have useful anti-HIV-1 properties.
authors.affiliation: Biotron Limited, Australian National University, ACT. gewart@biotron.com.au
authors.forename: Gary D
authors.initials: GD
authors.lastname: Ewart
authors.forename: Kerry
authors.initials: K
authors.lastname: Mills
authors.forename: Graeme B
authors.initials: GB
authors.lastname: Cox
authors.forename: Peter W
authors.initials: PW
authors.lastname: Gage
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001483:Base Sequence; D055592:Biophysical Phenomena; D001703:Biophysics; D004279:DNA, Viral / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D006367:HeLa Cells; D054298:Human Immunodeficiency Virus Proteins; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D000086082:Viroporin Proteins
chemical_list: D000584:Amiloride; D019380:Anti-HIV Agents; D004279:DNA, Viral; D054298:Human Immunodeficiency Virus Proteins; D007473:Ion Channels; D010446:Peptide Fragments; D011994:Recombinant Proteins; D054334:Viral Regulatory and Accessory Proteins; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins; C057360:5-(N,N-hexamethylene)amiloride; C039465:5-dimethylamiloride