Multicomponent Macrocyclic IL-17a Modifier.

IL-17a is a major inflammation target, with several approved antibodies in clinical use. Small-molecule IL-17a antagonists are an emerging hot topic, with the recent advancement of three compounds into clinical trials. Here, we describe the design, discovery, synthesis, and screening of macrocyclic compounds that bind to IL-17a. We found that all currently described IL-17a modifiers belong to the same pharmacophore model, likely resulting in a similar receptor binding mode on IL-17a. A pipeline of pharmacophore analysis, virtual screening, resynthesis, and protein biophysics resulted in a potent IL-17a macrocyclic modifier.