title: Potent anti-HIV (type 1 and type 2) activity of polyoxometalates: structure-activity relationship and mechanism of action.
abstract: A series of polyoxometalates have been synthesized and evaluated for their inhibitory effects on HIV-1(III(B)) and HIV-1(ROD) replication in MT-4 cells. All compounds showed activity against HIV-1 and HIV-2, but the antiviral potency of the heteropolytungstates varied considerably depending on their chemical structure. The antiviral activity of single, double, and triple Keggin-type of compounds against HIV-1(III(B)) replication was comparable (IC(50): 0.4-0.5 microgram/mL), whereas HIV-2(ROD) appeared to become less sensitive with the increasing number of Keggin structures per compound. The same trend was observed for single and double Dawson structures. Some of these compounds were examined for their inhibitory effect on the replication of HIV-1(RF) and SIV(MAC(251)) in MT-4 cells. Their anti-HIV-1(RF) and anti-SIV(MAC(251)) potencies were comparable to those for the HIV-1(III(B)) or HIV-2(ROD) strain, respectively. The polyoxometalates represent a class of polyanionic compounds, which block the binding of the envelope glycoprotein gp120 of HIV to CD4(+) cells. The compounds interfered with the binding of anti-CD4 mAb to the OKT4A/Leu3a epitope of the CD4 receptor, compound 24 being the most active in this regard, and inhibited the binding of anti-gp120 mAb to infected MT-4 cells. None of the polyoxometalates inhibited the binding of a specific CXCR4 mAb to SUP-T1 cells, suggesting that they do not interact with CXCR4, the main co-receptor for T-tropic HIV strains, and thus act as virus binding, and not as fusion, inhibitors.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium, USA. Myriam.Witvrouw@uz.kukleuven.ac.be
authors.forename: M
authors.initials: M
authors.lastname: Witvrouw
authors.forename: H
authors.initials: H
authors.lastname: Weigold
authors.forename: C
authors.initials: C
authors.lastname: Pannecouque
authors.forename: D
authors.initials: D
authors.lastname: Schols
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: G
authors.initials: G
authors.lastname: Holan
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D000939:Epitopes; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects*; D006801:Humans; D051379:Mice; D010087:Oxides / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014414:Tungsten / Q000737:chemistry* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D000939:Epitopes; D015699:HIV Envelope Protein gp120; C406225:Na16(Mn4(H2O)2(P2W15O56)2); D010087:Oxides; D014414:Tungsten