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 microM). 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.
Gammon
G
G
Department of Molecular Sciences, Xenova Ltd, Slough, Berks, GB.
Chandler
G
G
Depledge
P
P
Elcock
C
C
Wrigley
S
S
Moore
J
J
Cammarota
G
G
Sinigaglia
F
F
Moore
M
M
D000818:Animals; D001312:Aurintricarboxylic Acid / Q000494:pharmacology; D015704:CD4 Antigens / Q000378:metabolism*; D016264:Dextran Sulfate / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D010407:Penicillium / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014966:Xanthenes / Q000494:pharmacology*; D044004:Xanthones
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II; D011753:Pyrones; D014966:Xanthenes; D044004:Xanthones; C086647:vinaxanthone; D001312:Aurintricarboxylic Acid; C013444:citromycetin; D016264:Dextran Sulfate