Inhibition of human immunodeficiency virus activity by phosphorodithioate oligodeoxycytidine.
Phosphorothioate oligodeoxynucleotides exert a sequence-independent cytoprotective effect against human immunodeficiency virus type 1 (HIV-1). We now report that phosphorodithioate-containing oligodeoxycytidines are very potent inhibitors of HIV-1 reverse transcriptase in vitro, as they exhibit an increasing inhibitory effect with length and number of phosphorodithioate internucleotide linkages. This inhibitory effect can be at least 30-fold greater with phosphorodithioate oligodeoxycytidine than for the corresponding phosphorothioate analog of similar length. In cell culture, phosphorodithioate oligodeoxycytidines are active inhibitors of syncytia formation and effectively inhibit de novo infection of target cells by HIV-1. Moreover, comparative experiments show that a deoxycytidine phosphorodithioate 14-mer is as effective an inhibitor of de novo infection as a phosphorothioate-containing 28-mer. Such potent inhibition by oligomers of relatively short length makes dithioate analogs an additional class of potential therapeutic agents against acquired immunodeficiency syndrome.
Marshall
W S
WS
Department of Chemistry and Biochemistry, University of Colorado, Boulder 80309-0215.
Beaton
G
G
Stein
C A
CA
Matsukura
M
M
Caruthers
M H
MH
D000998:Antiviral Agents; D001483:Base Sequence; D002459:Cell Fusion / Q000187:drug effects; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015658:HIV Infections / Q000473:pathology; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000201:enzymology*; D008969:Molecular Sequence Data; D019384:Nucleic Acid Synthesis Inhibitors; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors; D013873:Thionucleotides / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D019384:Nucleic Acid Synthesis Inhibitors; D009838:Oligodeoxyribonucleotides; D018894:Reverse Transcriptase Inhibitors; D013873:Thionucleotides; D003841:Deoxycytidine; D054303:HIV Reverse Transcriptase