title: Role of cations in the interaction of pradimicins with HIV-1 envelope gp120.
abstract: Pradimicins (PRM) are a unique class of nonpeptidic carbohydrate-binding agents that inhibit HIV infection by efficiently binding to the HIV-1 envelope gp120 glycans in the obligatory presence of Ca(2+). Surface plasmon resonance (SPR) data revealed that addition of EDTA dose-dependently results in lower binding signals of PRM-A to immobilized gp120. Pradimicin derivatives that lack the free carboxylic acid group on the C-18 position failed to bind gp120 and were devoid of significant antiviral activity. Ca(2+) was much more efficient for PRM-A binding to gp120 than Cd(2+), Ba(2+) or Sr(2+). Instead, calcium could not be replaced by any other mono- (i.e. K(+)), di- (i.e. Cu(2+), Mg(2+), Mn(2+), Fe(2+), Zn(2+)) or trivalent (i.e. Al,(3+), Fe(3+)) cation without complete loss of gp120 binding. However, Zn(2+), Mg(2+) and Mn(2+) added to a Ca(2+)- pradimicin mixture, prevented pradimicin from efficient binding to gp120 glycans. These data suggest that these bivalent cations may bind to pradimicins but lead to pradimicin-cation complexes that are unable to further coordinate with the glycans of gp120. Thus, in order to afford antiviral activity, only a few cations can (i) bind to pradimicin to form a dimeric complex and (ii) subsequently coordinate the pradimicin/cation interaction with gp120 glycans.
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Hoorelbeke
authors.forename: Youngju
authors.initials: Y
authors.lastname: Kim
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Oki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Igarashi
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
mesh_terms: D018943:Anthracyclines / Q000737:chemistry* / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D002412:Cations / Q000737:chemistry*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D000095643:Pradimicins and Benanomicins
chemical_list: D018943:Anthracyclines; D019380:Anti-HIV Agents; D002412:Cations; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1; C058036:pradimicin A; D000095643:Pradimicins and Benanomicins