molecules of the month

11. The EMD Serono/Merck KGaA toll-like receptors TLR7/TLR8 inhibitor M5049 is an oral, twice-daily anti-inflammatory agent currently in a Ph. I trial for Lupus. The molecule potently blocks both synthetic ligands and natural endogenous RNA ligands such as microRNA and Alu RNA. TLR7 and TLR8 selective modulators (both agonists and antagonists) have been of significant recent interest due to the TLR’s key roles in immune signaling but have been challenging to develop since TLR7/8 are membrane proteins that are difficult to express, purify, and crystallize. The Serono team however was able to generate an interesting crystal structure showing that the molecule binds to the interface between two monomers, stabilizing an inactive dimer, preventing receptor activation.