title: Potent inhibition of HIV-1 entry by (s4dU)35.
abstract: We have previously reported the potent in vitro HIV-1 anti-reverse transcriptase activity of a 35-mer of 4-thio-deoxyuridylate [(s(4)dU)(35)]. In efforts to define its activity in a more physiological system, studies were carried out to determine the stage of viral infection that this compound mediates its anti-viral effect. Results of the studies reported herein show that (s(4)dU)(35) is nontoxic and is capable of inhibiting both single and multi-drug resistant HIV strains (IC(50): 0.8-25.4 microg/ml) in vitro. Besides its previously reported anti-RT activity, (s(4)dU)(35) mediated its antiviral action by preventing virus attachment (IC(50): 0.002-0.003 microg/ml), and was stable in vitro and slowly degraded by DNAses. Competition studies and fluorescence resonance energy transfer (FRET) experiments indicated that (s(4)dU)(35) preferentially binds to CD4 receptors, but not to CD48. Confocal laser scanning microscopy (CLSM) studies showed that (s(4)dU)(35) did not penetrate into the cells and colocalized with cell surface thioredoxin. Our studies identify (s(4)dU)(35) as a potential novel HIV entry inhibitor that may have utility as either a systemic antiretroviral or as a preventing agent for HIV transmission.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, H-4012 Debrecen, Nagyerdei krt. 98, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Horváth
authors.forename: Szilvia
authors.initials: S
authors.lastname: Tokés
authors.forename: Tracy
authors.initials: T
authors.lastname: Hartman
authors.forename: Karen
authors.initials: K
authors.lastname: Watson
authors.forename: Jim A
authors.initials: JA
authors.lastname: Turpin
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buckheit
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Sebestyén
authors.forename: János
authors.initials: J
authors.lastname: Szöllosi
authors.forename: Ilona
authors.initials: I
authors.lastname: Benko
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Bardos
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Dunn
authors.forename: László
authors.initials: L
authors.lastname: Fésüs
authors.forename: Ferenc D
authors.initials: FD
authors.lastname: Tóth
authors.forename: Janos
authors.initials: J
authors.lastname: Aradi
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000633:toxicity; D015704:CD4 Antigens / Q000378:metabolism; D002460:Cell Line; D003856:Deoxyuracil Nucleotides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D031541:Fluorescence Resonance Energy Transfer; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity*; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D018613:Microscopy, Confocal; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D013873:Thionucleotides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity
chemical_list: C500998:(s4dU)35; C009461:4-thio-2'-deoxyuridylate; D019380:Anti-HIV Agents; D015704:CD4 Antigens; D003856:Deoxyuracil Nucleotides; D018894:Reverse Transcriptase Inhibitors; D013873:Thionucleotides; D054303:HIV Reverse Transcriptase