title: Newly designed six-membered azasugar nucleotide-containing phosphorothioate oligonucleotides as potent human immunodeficiency virus type 1 inhibitors.
abstract: A series of modified oligonucleotides (ONs), characterized by a phosphorothioate (P S) backbone and a six-membered azasugar (6-AZS) as a sugar substitute in a nucleotide, were newly synthesized and assessed for their ability to inhibit human immunodeficiency virus type 1 (HIV-1) via simple treatment of HIV-1-infected cultures, without any transfection process. While unmodified P S ONs exhibited only minor anti-HIV-1 activity, the six-membered azasugar nucleotide (6-AZN)-containing P S oligonucleotides (AZPSONs) exhibited remarkable antiviral activity against HIV-1/simian-human immunodeficiency virus (SHIV) replication and syncytium formation (50% effective concentration = 0.02 to 0.2 microM). The AZPSONs exhibited little cytotoxicity at concentrations of up to 100 microM. DBM 2198, one of the most effective AZPSONs, exhibited antiviral activity against a broad spectrum of HIV-1, including T-cell-tropic, monotropic, and even drug-resistant HIV-1 variants. The anti-HIV-1 activities of DBM 2198 were similarly maintained in HIV-1-infected cultures of peripheral blood mononuclear cells. When we treated severely infected cultures with DBM 2198, syncytia disappeared completely within 2 days. Taken together, our results indicate that DBM 2198 and other AZPSONs may prove useful in the further development of safe and effective AIDS-therapeutic drugs against a broad spectrum of HIV-1 variants.
authors.affiliation: Department of Biological Science, Sungkyunkwan University, Jangan-gu, Suwon, Gyounggi-do, South Korea.
authors.forename: Dong-Seong
authors.initials: DS
authors.lastname: Lee
authors.forename: Kyeong-Eun
authors.initials: KE
authors.lastname: Jung
authors.forename: Cheol-Hee
authors.initials: CH
authors.lastname: Yoon
authors.forename: Hong
authors.initials: H
authors.lastname: Lim
authors.forename: Yong-Soo
authors.initials: YS
authors.lastname: Bae
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D014644:Genetic Variation; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D015394:Molecular Structure; D009841:Oligonucleotides / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013873:Thionucleotides / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D009841:Oligonucleotides; D013873:Thionucleotides; D054303:HIV Reverse Transcriptase