Role of cations in the interaction of pradimicins with HIV-1 envelope gp120.

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,sup>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