title: [Inhibition of herpes simplex virus helicase UL9 by netropsin derivatives and antiviral activities of bis-netropsins].
abstract: Data obtained show that antiviral activities of bis-linked netropsin derivatives are targeted by specific complexes formed by helicase UL9 of herpes simplex virus type 1 with viral DNA replication origins, represented by two OriS sites and one OriL site. According to the results of footprinting studies bis-netropsins get bound selectively to an A+T-cluster which separates interaction sites I and II for helicase UL9 in OriS. Upon binding to DNA bis-netropsins stabilize a structure of the A+T-cluster and inhibit thermal fluctuation-induced opening of AT- base pairs which is needed for local unwinding of DNA by helicase UL9. Kinetics of ATP-dependent DNA unwinding in the presence and absence of Pt-bis-netropsin are studied by measuring the efficiency of Forster resonance energy transfer (FRET) between the fluorescent probes attached covalently to 3?- and 5?-ends of the oligonucleotides in the minimal OriS duplex. Pt-bis-netropsin and related molecules inhibit unwinding of OriS duplex by helicase UL9. Pt-bis-netropsin is also able to reduce the rate of unwinding of the AT- rich hairpin formed by the upper strand in the minimal OriS duplex. The antiviral activities and toxicity of bis-linked netropsin derivatives are studied in cell cultured experiments and experiments with animals infected by herpes virus.
authors.forename: N P
authors.initials: NP
authors.lastname: Bazhulina
authors.forename: A N
authors.initials: AN
authors.lastname: Surovaia
authors.forename: Ia G
authors.initials: IaG
authors.lastname: Gurskiĭ
authors.forename: V L
authors.initials: VL
authors.lastname: Andronova
authors.forename: V S
authors.initials: VS
authors.lastname: Arkhipova
authors.forename: M V
authors.initials: MV
authors.lastname: Golovkin
authors.forename: A M
authors.initials: AM
authors.lastname: Nikitin
authors.forename: G A
authors.initials: GA
authors.lastname: Galegov
authors.forename: S L
authors.initials: SL
authors.lastname: Gorokhovskiĭ
authors.forename: G V
authors.initials: GV
authors.lastname: Gurskiĭ
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004261:DNA Replication / Q000187:drug effects*; D004279:DNA, Viral / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006561:Herpes Simplex / Q000188:drug therapy / Q000201:enzymology; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009429:Netropsin / Q000031:analogs & derivatives / Q000494:pharmacology*; D014709:Vero Cells; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D014764:Viral Proteins; C064565:UL9 protein, Human herpesvirus 1; D009429:Netropsin