Small molecules that selectively block RNA binding of HIV-1 Rev protein inhibit Rev function and viral production.
Replication of RNA viruses, such as the human immunodeficiency virus (HIV), is dependent upon multiple specific interactions between viral RNAs and viral and cellular proteins. A small molecule that interferes specifically with one or more of these RNA-protein interactions could be an efficacious antiviral agent. Here we show that certain aminoglycoside antibiotics, in particular neomycin B, can block binding of the HIV Rev protein to its viral RNA recognition element. Inhibition appears to be highly selective, resulting from competitive binding of the drug to a small viral RNA region within the Rev-binding site. We further demonstrate that neomycin B can specifically antagonize Rev function in vitro and in vivo and can inhibit production of HIV. Our results establish the feasibility for developing antiviral drugs that act by selectively blocking RNA-protein interactions.
Zapp
M L
ML
Program in Molecular Medicine, University of Massachusetts Medical Center, Worcester 01605.
Stern
S
S
Green
M R
MR
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D003001:Cloning, Molecular; D005601:Framycetin / Q000494:pharmacology*; D015694:Gene Products, rev / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007612:Kanamycin / Q000494:pharmacology; D008969:Molecular Sequence Data; D009000:Monocytes; D009690:Nucleic Acid Conformation; D012322:RNA Precursors / Q000378:metabolism; D015347:RNA Probes; D012326:RNA Splicing; D012367:RNA, Viral / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects*; D054321:rev Gene Products, Human Immunodeficiency Virus
D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D015694:Gene Products, rev; D012322:RNA Precursors; D015347:RNA Probes; D012367:RNA, Viral; D011994:Recombinant Proteins; D054321:rev Gene Products, Human Immunodeficiency Virus; D005601:Framycetin; D007612:Kanamycin