Role of Cations in the Interaction of Pradimicins with HIV-1 Envelope gp120

Bart      Hoorelbeke; Youngju      Kim; Toshikazu      Oki; Yasuhiro      Igarashi; Jan      Balzarini

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 Ca²⁺. 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. Ca²⁺ was much more efficient for PRM-A binding to gp120 than Cd²⁺, Ba²⁺ or Sr²⁺. Instead, calcium could not be replaced by any other mono- (i.e. K⁺), di- (i.e. Cu²⁺, Mg²⁺, Mn2+, Fe²⁺, Zn²⁺) or trivalent (i.e. Al,sup>3+, Fe³⁺) cation without complete loss of gp120 binding. However, Zn²⁺, Mg²⁺ and Mn²⁺ added to a Ca²⁺- 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