title: Structure-activity of inhibition of HIV-1 integrase and virus replication by G-quartet oligonucleotides.
abstract: As novel anti-HIV agents, the G-tetrad-forming oligonucleotides have been explored for their structure-activity relations with regard to inhibition of integrase (IN) (N. Jing, Expert Opin. Investig. Drugs (2000) 9, 1777-1785). We have now developed two families of G-quartet oligonucleotides: T40217-T40222, with potential formation of a tail-to-tail G-quartet dimer, and T40224-T40227, with phosphorothioate (PT) linkages in the guanine loops. The results obtained from biophysical measurements and the assays of the inhibition of HIV-1 IN and virus replication demonstrated that an increase in the length of the G-quartet structure from a monomer (15A) to a tail-to-tail dimer (47A) does not distinctly disrupt the inhibition of HIV-1 IN activity or the inhibition of HIV-1 replication in cell cultures. G-quartet oligonucleotides were observed to induce molecular aggregation of HIV-1 IN and interrupt the binding of viral DNA to HIV-1 IN. Also, PT substitutions did not confer any advantages compared with the regular phosphodiesters for the inhibition of HIV-1 replication by intramolecular G-quartets. The G-quartet motif is the primary requirement for the remarkable nuclease resistance and pronounced biological efficacy of these oligonucleotides.
authors.affiliation: Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA. njing@bcm.tmc.edu
authors.forename: N
authors.initials: N
authors.lastname: Jing
authors.forename: C
authors.initials: C
authors.lastname: Marchand
authors.forename: Y
authors.initials: Y
authors.lastname: Guan
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: L
authors.initials: L
authors.lastname: Pallansch
authors.forename: C
authors.initials: C
authors.lastname: Lackman-Smith
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D002460:Cell Line; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019428:HIV Integrase Inhibitors; D009838:Oligodeoxyribonucleotides; D019427:HIV Integrase