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.
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