Phosphorodithioate oligodeoxynucleotide analogs as inhibitors of HIV-1 reverse transcriptase and viral replication.

Important note: Information in this article was accurate in 1993. The state of the art may have changed since the publication date.

Phosphorodithioate oligodeoxynucleotide analogs as inhibitors of HIV-1 reverse transcriptase and viral replication.

Diss Abstr Int [B]; 52(9):4710 1992. Unique Identifier : AIDSLINE ICDB/93682297
Marshall WS; Univ. of Colorado at Boulder

Abstract: Phosphorodithioate DNA is a nucleic acid analog which contains internucleotide phosphodiester groups having sulfur at the two nonlinking positions. We have synthesized a number of dithioate oligodeoxynucleotide analogs and examined the potential anti-HIV activity of these derivatives. Oligodeoxycytidine analogs exhibit strong inhibitory properties against HIV-1 reverse transcriptase, a viral enzyme which is essential for HIV replication. This inhibition is dependent on both the number of dithioate linkages and the length of dithioate oligomer analog. A kinetic investigation into the mechanism of this inhibition suggests that dithioate oligomers bind to the active site for primer-template and competitively inhibit enzyme activity. An extension of these studies in cell culture experiments reveals that dithioate oligodeoxycytidine analogs also potently inhibit HIV-1 replication. In all cases, a comparative analysis with phosphorothioate equivalents indicates that dithioates are much better inhibitors and are able to inhibit potently at relatively short oligomer length. Inhibition of HIV-1 reverse transcriptase by dithioate oligodeoxynucleotides appears to be a general phenomenon as all of the nucleotide base sequences examined inhibit its activity. Dithioate primer analogs are also active substrates for HIV-1 reverse transcriptase when duplexed with natural DNA. By rationally designing a dithioate oligomer analog which is a pivotal component of reverse transcription during viral replication, we discovered an extremely potent HIV-1 reverse transcriptase inhibitor which has the potential to act against the virus at multiple stages during its replicative cycle. Thus, phosphorodithioate oligodeoxynucleotide analogs may represent a novel class of experimental therapeutic agents against AIDS. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD92-06621).

Keywords: Base Sequence HIV Infections/*METABOLISM/MICROBIOLOGY HIV-1/*DRUG EFFECTS/ENZYMOLOGY/PHYSIOLOGY Oligodeoxyribonucleotides/*PHARMACOLOGY RNA-Directed DNA Polymerase/*METABOLISM Virus Replication/*DRUG EFFECTS THESIS
930930
M9391186

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