Abstract
Despite more than 25 years of research, the molecular targets of quinoline-3-carboxamides have been elusive although these compounds are currently in Phase II and III development for treatment of autoimmune/inflammatory diseases in humans. Using photoaffinity cross-linking of a radioactively labelled quinoline-3-carboxamide compound, we could determine a direct association between human S100A9 and quinoline-3-carboxamides. This interaction was strictly dependent on both Zn++ and Ca++. We also show that S100A9 in the presence of Zn++ and Ca++ is an efficient ligand of receptor for advanced glycation end products (RAGE) and also an endogenous Toll ligand in that it shows a highly specific interaction with TLR4/MD2. Both these interactions are inhibited by quinoline-3-carboxamides. A clear structure-activity relationship (SAR) emerged with regard to the binding of quinoline-3-carboxamides to S100A9, as well as these compounds potency to inhibit interactions with RAGE or TLR4/MD2. The same SAR was observed when the compound's ability to inhibit acute experimental autoimmune encephalomyelitis in mice in vivo was analysed. Quinoline-3-carboxamides would also inhibit TNFα release in a S100A9-dependent model in vivo, as would antibodies raised against the quinoline-3-carboxamide–binding domain of S100A9. Thus, S100A9 appears to be a focal molecule in the control of autoimmune disease via its interactions with proinflammatory mediators. The specific binding of quinoline-3-carboxamides to S100A9 explains the immunomodulatory activity of this class of compounds and defines S100A9 as a novel target for treatment of human autoimmune diseases.
Highlights
The medical need for novel treatments of human autoimmune/inflammatory disease is high
What molecules and mechanisms underlie the development of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus are largely unknown
We show that these Q compounds bind to a molecule called S100A9 that is expressed on the surface of various monocyte populations in the peripheral blood
Summary
The medical need for novel treatments of human autoimmune/inflammatory disease is high. Quinoline-3-carboxamides (Q compounds) have been explored as treatments for autoimmune/inflammatory diseases in humans. Q compounds are unique in that they have a potent effect on disease development in several animal models of autoimmune/inflammatory disease without inducing suppression of adaptive immunity [7,8,9,10]. From these studies, it was obvious that the molecular target for Q compounds was novel since no known signalling pathway could explain the experimental data obtained. It appeared likely that the mode of action of Q compounds would be targeting early stages of immune stimulation that could be common for many autoimmune disorders while keeping the immune effector stage intact
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