Potent and specific inhibition of HIV envelope-mediated cell fusion and virus binding by G quartet-forming oligonucleotide (ISIS 5320).
We have previously reported identification of a phosphorothioate oligonucleotide TTGGGGTT (ISIS 5320) as a potent inhibitor of HIV infection in vitro. The oligonucleotide forms a parallel-stranded, tetrameric guanosine quartet (G-quartet) structure that specifically binds to the HIV envelope glycoprotein (gp120) and inhibits both cell-to-cell and virus-to-cell infection at submicromolar concentrations. In the current study we demonstrate that the tetramer inhibits the infection of laboratory-derived isolates of HIV-1 and HIV-2 in a variety of phenotypically distinct, established human cell lines and a panel of biologically diverse clinical isolates in fresh human peripheral blood lymphocytes and macrophages. The compound was also active against all drug-resistant virus isolates tested. In combination with AZT, ISIS 5320 exhibits additive to slightly synergistic anti-HIV activity. Cell-based mechanism of action studies demonstrate that the compound inhibits the binding of infectious virus and virus-infected cells to uninfected target cells by binding to the cationic V3 loop of the envelope glycoprotein. The G-quartet structure is a potential candidate for use in anti-HIV chemotherapy.
Buckheit
R W
RW
Southern Research Institute-Frederick Research Center, Maryland 21701.
Roberson
J L
JL
Lackman-Smith
C
C
Wyatt
J R
JR
Vickers
T A
TA
Ecker
D J
DJ
D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D002459:Cell Fusion / Q000187:drug effects; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D013873:Thionucleotides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015215:Zidovudine / Q000008:administration & dosage
D000998:Antiviral Agents; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D013873:Thionucleotides; C085909:oligonucleotide 5320; D015215:Zidovudine