Characterization of siamycin I, a human immunodeficiency virus fusion inhibitor.

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 mu M, and the concentration resulting in a 50% decrease in cell viability in the absence of viral infection is 150 mu M in CEM-SS cells. Siamycin I inhibits fusion between C8166 cells and CEM-SS cells chronically infected with NN (50% effective dose of 0.08 mu M) 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.