title: Structure-activity relationships and mode of action of 5-mercapto-substituted oligo- and polynucleotides as antitemplates inhibiting replication of human immunodeficiency virus type 1.
abstract: Introduction of a reactive 5-mercapto group into some of the cytosine and/or uracil bases of various oligo- and 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/p51 HIV-1 recombinant reverse transcriptase (RT) than against the DNA polymerase alpha 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 micrograms/ml or 0.019 microM), while showing low cytotoxicity (greater than 100 micrograms/ml). The corresponding unmodified poly(dC) showed no anti-HIV-1 activity at 50 micrograms/ml but had pronounced cytotoxicity. MPdC was also a potent inhibitor of HIV-1 RT (50% inhibitory concentration, 0.30 micrograms/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., tRNA(3Lys). 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.
authors.affiliation: Department of Medicinal Chemistry, State University of New York, Buffalo, Amherst 14260, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Bardos
authors.forename: R F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: K H
authors.initials: KH
authors.lastname: Ling
authors.forename: A R
authors.initials: AR
authors.lastname: Heider
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004257:DNA Polymerase II / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D011119:Polynucleotides / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D011119:Polynucleotides; D013438:Sulfhydryl Compounds; D004257:DNA Polymerase II