title: [HIV-inhibiting activity of polyanion matrices and related substances containing adamantane and norbornene pharmacophores].
abstract: Analysis of molecular mechanisms of HIV-infection and targets for therapeutic intervention allowed to offer strategy for design of new effective anti-HIV/AIDS agents on the basis of two key principles: 1) intervention to infectious process beginning from the earliest stages of the virus penetration into cells; 2) blockade of not only one but several molecular targets of the HIV life cycle. The paper presents the results of the in vitro investigation of the anti-HIV activity (against several HIV-1 strains, including AZT-resistant ones) of new generation complex substances synthesized with application of the molecular substrategy for bifunctional inhibitors on the basis of a combination of nonspecific antiviral active polymeric anions with selective virus sensitive membranotropic pharmacophores of the adamantane and norbornene lines. The HIV-1 inhibiting potential of polymeric carboxylic acids (PKA) of various nature: synthetic polymeric analogues of succinic acid and carboxymethylated dextran was evaluated. It was shown that the antiviral action of PKA is located at the initial stages of HIV-1 penetration into cells and is markedly defined by balance of electrostatic activity and conformational mobility of the macromolecules. This corresponds to the evidence of the negatively charged macromolecules ability to bind the positively charged V3 loop within the viral protein gp120, preventing the HIV-1 adsorption on the surface of permissive cells. Chemical conjugation of the PKA with derivatives of the adamantane (amantadine and rimantadine analogues) or norbornene (related to deitiforin and natural bicyclic therpenoids) via spacer groups provides synergistic elevation of the anti-HIV-1 activity, first of all for the flexible chain PKA. The obtained result experimentally confirmed the theoretically predicted expansion of the anti-HIV-1 action of the bifunctional kind antivirals due to cooperation of the electrostatic potential of PKA with the virus specific hydrophobic activity needed to block postadsorption events of the HIV-1 life cycle, including both the virus penetration into cells and the virus posterity release from the infected cells. Additional cooperation of PKA with some special vectors targeted towards "Raft" domains of cellular membranes, epicentres for natural location of initial and completed stages of the HIV-1 replication cycle was also shown promising. The structure-function optimized samples exhibit high indexes of anti-HIV-1 selectivity up to IS50 = 10000.
authors.affiliation: State Research Center of Virology and Biotechnology "Vector", Koltsovo, Novosibirsk Region.
authors.forename: D I
authors.initials: DI
authors.lastname: Timofeev
authors.forename: N G
authors.initials: NG
authors.lastname: Perminova
authors.forename: A V
authors.initials: AV
authors.lastname: Serbin
authors.forename: Ia Iu
authors.initials: IaIu
authors.lastname: Kiseleva
authors.forename: V V
authors.initials: VV
authors.lastname: Nekliudov
authors.forename: G Iu
authors.initials: GIu
authors.lastname: Vatolin
authors.forename: L I
authors.initials: LI
authors.lastname: Kas'ian
authors.forename: T S
authors.initials: TS
authors.lastname: Grebinik
authors.forename: I V
authors.initials: IV
authors.lastname: Timofeev
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000838:Anions; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002264:Carboxylic Acids / Q000737:chemistry*; D002478:Cells, Cultured; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009636:Norbornanes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011108:Polymers; D013329:Structure-Activity Relationship; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D000838:Anions; D019380:Anti-HIV Agents; D002264:Carboxylic Acids; D009636:Norbornanes; D011108:Polymers; D015215:Zidovudine; D000218:Adamantane
vernacular_title: VICh-ingibiruiushchaia aktivnost' polianionnykh matrits i soedineniĭ na ikh osnove, soderzhashchikh adamantanovye i norbornenovye farmakofory.