title: Characterization of siamycin I, a human immunodeficiency virus fusion inhibitor.
abstract: The human immunodeficiency virus (HIV) fusion inhibitor siamycin I, a 21-residue tricyclic peptide, was identified from a Streptomyces culture by using a cell fusion assay involving cocultivation of HeLa-CD4+ cells and monkey kidney (BSC-1) cells expressing the HIV envelope gp160. Siamycin I is effective against acute HIV type 1 (HIV-1) and HIV-2 infections, with 50% effective doses ranging from 0.05 to 5.7 microM, and the concentration resulting in a 50% decrease in cell viability in the absence of viral infection is 150 microM in CEM-SS cells. Siamycin I inhibits fusion between C8166 cells and CEM-SS cells chronically infected with HIV (50% effective dose of 0.08 microM) but has no effect on Sendai virus-induced fusion or murine myoblast fusion. Siamycin I does not inhibit gp120 binding to CD4 in either gp120- or CD4-based capture enzyme-linked immunosorbent assays. Inhibition of HIV-induced fusion by this compound is reversible, suggesting that siamycin I binds noncovalently. An HIV-1 resistant variant was selected by in vitro passage of virus in the presence of increasing concentrations of siamycin I. Drug susceptibility studies on a chimeric virus containing the envelope gene from the siamycin I-resistant variant indicate that resistance maps to the gp160 gene. Envelope-deficient HIV complemented with gp160 from siamycin I-resistant HIV also displayed a resistant phenotype upon infection of HeLa-CD4-LTR-beta-gal cells. A comparison of the DNA sequences of the envelope genes from the resistant and parent viruses revealed a total of six amino acid changes. Together these results indicate that siamycin I interacts with the HIV envelope protein.
authors.affiliation: Department of Virology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA.
authors.forename: P F
authors.initials: PF
authors.lastname: Lin
authors.forename: H
authors.initials: H
authors.lastname: Samanta
authors.forename: C M
authors.initials: CM
authors.lastname: Bechtold
authors.forename: C A
authors.initials: CA
authors.lastname: Deminie
authors.forename: A K
authors.initials: AK
authors.lastname: Patick
authors.forename: M
authors.initials: M
authors.lastname: Alam
authors.forename: K
authors.initials: K
authors.lastname: Riccardi
authors.forename: R E
authors.initials: RE
authors.lastname: Rose
authors.forename: R J
authors.initials: RJ
authors.lastname: White
authors.forename: R J
authors.initials: RJ
authors.lastname: Colonno
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D015704:CD4 Antigens / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D004352:Drug Resistance, Microbial; D006678:HIV / Q000187:drug effects* / Q000302:isolation & purification; D019302:HIV Envelope Protein gp160 / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008561:Membrane Fusion / Q000187:drug effects*; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides; D016865:Reassortant Viruses / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology
chemical_list: D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D015704:CD4 Antigens; D019302:HIV Envelope Protein gp160; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C094260:siamycin I