Oligonucleotides containing modified bases. I. Inhibition of DNA and RNA polymerases by partially thiolated oligocytidylic acids

Ho, Yau-Kwan; Kung, M.P.; Bardos, Thomas J.

doi:10.1016/0006-291x(76)90207-2

Cited by 8 publications

(2 citation statements)

References 12 publications

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“…5-Thiolated oligocytidylates were less active than MPC, and their inhibitory activity against DNA and RNA polymerases increased with increasing chain length (23).…”

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confidence: 93%

Structure-activity relationships and mode of action of 5-mercapto-substituted oligo- and polynucleotides as antitemplates inhibiting replication of human immunodeficiency virus type 1

Bardos

Schinazi

Ling

et al. 1992

Antimicrob Agents Chemother

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Introduction of a reactive 5-mercapto group into some of the cytosine and/or uracil bases of various oligoand polynucleotides by partial thiolation resulted in several potent inhibitors of the replication of human immunodeficiency virus type 1 (HIV-1) in primary human lymphocytes. These compounds exhibited little if any toxicity against uninfected peripheral blood mononuclear cells and showed 15 to 75 times higher antitemplate activity against a p66/p5i HIV-1 recombinant reverse transcriptase (RT) than against the DNA polymerase a from human lymphocytes. In contrast, the unthiolated oligo-and polynucleotides are void of antitemplate activity, and their apparent inhibitory effect on HIV-1 closely paralleled their toxicity for the cells. Partially thiolated poly(dC) (MPdC) was the most potent of all the compounds tested against HIV-1 in peripheral blood mononuclear cells (50% effective concentration, 1.8 ,ug/ml or 0.019 ,uM), while showing low cytotoxicity (>100 ,ug/ml). The corresponding unmodified poly(dC) showed no anti-HIV-1 activity at 50 ,ug/ml but had pronounced cytotoxicity. MPdC was also a potent inhibitor of HIV-1 RT (50% inhibitory concentration, 0.30 ,ug/ml). The inhibitory activities of thiolated homooligo(dCs) against both HIV-1 replication and HIV-1 RT increased with increasing chain length. The heterooligonucleotides included in this study were designed as structural analogs of portions of the natural primer of HIV-1 RT, i.e., tRNArYs. An 18-mer analog of the 3' terminus, complementary (antisense) to the primer-binding site of the HIV-1 genome, was attached to an oligo(dC) tail and 5-thiolated; this increased its activity and decreased its toxicity. This compound will serve as a new lead in the development of more effective antitemplates against HIV-1.

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