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: P F Lin, H Samanta, C M Bechtold, C A Deminie, A K Patick, M Alam, K Riccardi, R E Rose, R J White, R J Colonno
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 40 Issue 1 Pg. 133-8 (Jan 1996) ISSN: 0066-4804 [Print] United States
• PMID: 8787894 (Publication Type: Journal Article)

Chemical References

• Anti-Bacterial Agents
• Antiviral Agents
• CD4 Antigens
• HIV Envelope Protein gp160
• Intercellular Signaling Peptides and Proteins
• Peptides
• siamycin I

Topics

• Anti-Bacterial Agents (pharmacology)
• Antiviral Agents (pharmacology)
• Base Sequence
• CD4 Antigens (drug effects, metabolism)
• Cell Line
• Drug Resistance, Microbial
• HIV (drug effects, isolation & purification)
• HIV Envelope Protein gp160 (drug effects, genetics)
• HeLa Cells
• Humans
• Intercellular Signaling Peptides and Proteins
• Membrane Fusion (drug effects)
• Molecular Sequence Data
• Mutation
• Peptides
• Reassortant Viruses (drug effects)
• T-Lymphocytes (drug effects, virology)