Selective inhibition of the membrane attack complex of complement by low molecular weight components of the aurin tricarboxylic acid synthetic complex.
Complement plays a vital role in both the innate and adaptive immune systems. It recognizes a target, opsonizes it, generates anaphylatoxins, and directly kills cells through the membrane attack complex (MAC). This final function, which assembles C5b-9(n) on viable cell surfaces, can kill host cells through bystander lysis. Here we identify for the first time compounds that can inhibit bystander lysis while not interfering with the other essential functions of complement. We show that aurin tricarboxylic acid (ATA), aurin quadracarboxylic acid (AQA), and aurin hexacarboxylic acid (AHA), block the addition of C9 to C5b-8 so that the MAC cannot form. These molecules inhibit hemolysis of human, rat, and mouse red cells with a half maximal inhibitory concentration (IC(50)) in the nanomolar range. When given orally to Alzheimer disease type B6SJL-Tg mice, they inhibit MAC formation in serum and improve memory retention. On autopsy, they show no evidence of harm to any organ. Aurin tricarboxylic acid, aurin quadracarboxylic acid, and aurin hexacarboxylic acid may be effective therapeutic agents in Alzheimer disease and other degenerative disorders where self damage from the MAC occurs.
Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, Canada.
Moonhee
M
Lee
Jian-Ping
JP
Guo
Claudia
C
Schwab
Edith G
EG
McGeer
Patrick L
PL
McGeer
D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001312:Aurintricarboxylic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D024201:Bystander Effect / Q000187:drug effects; D003165:Complement System Proteins / Q000737:chemistry / Q000187:drug effects*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D012459:Salicylates / Q000138:chemical synthesis / Q000494:pharmacology*
D012459:Salicylates; C577562:aurin hexacarboxylic acid; C577561:aurin quadracarboxylic acid; D001312:Aurintricarboxylic Acid; D003165:Complement System Proteins