title: Anti-human immunodeficiency virus (HIV) drug HOE/BAY946 increases membrane hydrophobicity of human lymphocytes and specifically suppresses HIV-protein synthesis.
abstract: The polysulfated polyxylan HOE/BAY946, which has been tested in two pilot studies in ARC/AIDS patients and in asymptomatic HIV carries in Germany, was believed to act by inhibiting virus attachment to the cell. However, the drug was also found to reduce the amount of HIV particles released from infected peripheral blood mononuclear cells (PBMC) in vitro. Furthermore, preincubation of PBMC with the drug led to a partial inhibition of a following HIV infection, suggesting that the drug also affects virus entry. Electron Paramagnetic Resonance (EPR) measurements on uninfected human lymphocytes using 5-proxyl-nonane as spin label demonstrated smaller hyperfine coupling constant (aN) values in the presence of HOE/BAY946 or dextran sulfate 5000. Accordingly, h-1p/h-1H ratios were decreased, indicating increased plasma membrane hydrophobicity and a membrane-stabilizing effect of the drugs. Culture of the chronically HIV-infected monocytic cell line U937/HIV-2D194 in the presence of HOE/BAY946 specifically and drastically reduced the release of virions and the intracellular synthesis of viral proteins as determined by radioimmunoprecipitation and reverse transcriptase assays. In conclusion, although the EPR studies showed a physico-chemical effect on membrane polarity, HOE/BAY946 and dextran sulfate clearly affect processes beyond the cell membrane. Thus, in contrast to previous reports suggesting that polysulfated sugars affect HIV only by inhibiting virus binding to uninfected cells, they clearly inhibit HIV in infected cells as well and appear to have a pleiotropic mode of action. Such drugs may be less likely to result in viral resistance after prolonged application than substances acting only on one step in the life cycle of the virus.
authors.affiliation: Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Frankfurt, Federal Republic of Germany.
authors.forename: L
authors.initials: L
authors.lastname: Biesert
authors.forename: M
authors.initials: M
authors.lastname: Adamski
authors.forename: G
authors.initials: G
authors.lastname: Zimmer
authors.forename: H
authors.initials: H
authors.lastname: Suhartono
authors.forename: J
authors.initials: J
authors.lastname: Fuchs
authors.forename: U
authors.initials: U
authors.lastname: Unkelbach
authors.forename: R J
authors.initials: RJ
authors.lastname: Mehlhorn
authors.forename: K
authors.initials: K
authors.lastname: Hideg
authors.forename: R
authors.initials: R
authors.lastname: Milbradt
authors.forename: H
authors.initials: H
authors.lastname: Rübsamen-Waigmann
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D006678:HIV / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000382:microbiology*; D010426:Pentosan Sulfuric Polyester; D011134:Polysaccharides / Q000494:pharmacology*; D012995:Solubility; D014764:Viral Proteins / Q000096:biosynthesis*; D014771:Virion / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D011134:Polysaccharides; D014764:Viral Proteins; D010426:Pentosan Sulfuric Polyester