Antimalarial Drugs as Immune Modulators: New Mechanisms for Old Drugs.
The best known of the naturally occurring antimalarial compounds are quinine, extracted from cinchona bark, and artemisinin (qinghao), extracted from Artemisia annua in China. These and other derivatives are now chemically synthesized and remain the mainstay of therapy to treat malaria. The beneficial effects of several of the antimalarial drugs (AMDs) on clinical features of autoimmune disorders were discovered by chance during World War II. In this review, we discuss the chemistry of AMDs and their mechanisms of action, emphasizing how they may impact multiple pathways of innate immunity. These pathways include Toll-like receptors and the recently described cGAS-STING pathway. Finally, we discuss the current and future impact of AMDs on systemic lupus erythematosus, rheumatoid arthritis, and devastating monogenic disorders (interferonopathies) characterized by expression of type I interferon in the brain.
Division of Rheumatology, Department of Medicine, University of Washington, Seattle, Washington 98195; email jiean@uw.edu.
Jie
J
An
Department of Bioengineering.
Mark
M
Minie
Department of Chemistry.
Tomikazu
T
Sasaki
Department of Microbiology, and.
Joshua J
JJ
Woodward
Division of Rheumatology, Department of Medicine, University of Washington, Seattle, Washington 98195; email jiean@uw.edu.|Department of Immunology, University of Washington, Seattle, Washington 98195; email: meminie@uw.edu , sasaki@chem.washington.edu , jjwoodwa@uw.edu , elkon@uw.edu.
Keith B
KB
Elkon
D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001327:Autoimmune Diseases / Q000188:drug therapy*; D001343:Autophagy / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D056747:Immunomodulation / Q000187:drug effects*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy; D008565:Membrane Proteins / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
D000166:Acridines; D000962:Antimalarials; D037621:Artemisinins; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; D011804:Quinolines; D051193:Toll-Like Receptors; C532857:STING1 protein, human; D000099197:STING Protein; C031327:artemisinin; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
Toll-like receptors; autoimmunity; cGAS; innate immunity; rheumatoid arthritis; systemic lupus erythematosus