A fungal metabolite which inhibits the interaction of CD4 with major histocompatibility complex‐encoded class II molecules

CD4, a cell‐surface glycoprotein expressed on a subpopulation of T cells, is the receptor for class II molecules of the major histocompatibility complex (MHC II) and a receptor for the envelope glycoprotein (gp 120) of human immunodeficiency virus‐1 (HIV‐1). Screening of microbial metabolites for CD4‐binding activity using an enzyme‐linked immunosorbent assay based on the binding of the CD4‐specific monoclonal antibody (mAb), anti‐Leu3a, identified a family of compounds comprising several novel polyketides. The parent compound (411F, Vinaxanthone) is a C28 molecule probably arising from a dimerization of two C14 polyketide units. It strongly inhibited the interaction of anti‐Leu 3a and that of several other D1/D2 epitope‐specific mAb with CD4, but only weakly inhibited the binding of HIV‐1 gp120. Binding of a representative MHC class II molecule, HLA‐DRB*0401, was also inhibited by 411F with a comparable inhibitory concentration (IC50 = 1 μM). In functional assays 411F inhibited antigen‐induced CD4‐dependent T cell proliferative responses of peripheral blood mononuclear cells. At the clonal level 411F exhibited selectivity in that the compound inhibited peptide‐induced CD4+ T cell proliferative responses but not alloantigen‐induced CD8+ T cell proliferation. It is hypothesized that 411F, a polyanionic compound in aqueous solution at neutral pH, inhibits CD4‐dependent functions by binding over a broad area of the positively charged amino‐terminal D1 and D2 domains implicated in the interaction with MHC II molecules. 411F has the potential for development as an immunosuppressive agent with a novel mechanism of action.