The strand transfer oligonucleotide inhibitors of HIV-integrase.
Retroviral integrase participates in two catalytic reactions, which require interactions with the two ends of the viral DNA in the 3'processing reaction, and with a targeted host DNA in the strand transfer reaction. The 3'-hydroxyl group of 2'-deoxyadenosine resulting from the specific removing of GT dinucleotide from the viral DNA in the processing reaction provides the attachment site for the host DNA in a transesterification reaction. We synthesized oligonucleotides (ONs) of various lengths that mimic the processed HIV-1 U5 terminus of the proviral long terminal repeat (LTR) and are ended by 2'-deoxyadenosine containing a 3'-O-phosphonomethyl group. The duplex stability of phosphonomethyl ONs was increased by covalent linkage of the modified strand with its complementary strand by a triethylene glycol loop (TEG). Modified ONs containing up to 10 bases inhibited in vitro the strand transfer reaction catalyzed by HIV-1 integrase at nanomolar concentrations.
Snásel
Jan
J
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague 6, Czech Republic.
Rosenberg
Ivan
I
Paces
Ondrej
O
Pichová
Iva
I
D019427:HIV Integrase / Q000187:drug effects; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D018716:Molecular Mimicry; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000494:pharmacology*; D017976:Phosphorus Acids
D019428:HIV Integrase Inhibitors; D009841:Oligonucleotides; D017976:Phosphorus Acids; D019427:HIV Integrase