Chiral imidazoquinolines show stereochemistry-dependent TLR7/8 agonism and antagonism
- A library of chiral imidazoquinolines was made and profiled in HEK-Blue hTLR7 and hTLR8 reporter assays.
- The SAR identified a potent dual TLR7/8 agonist and, from the same family, a dual antagonist.
- Activity depended on stereochemistry, likely because the two enantiomers interact differently in the TLR7/8 binding pocket.
💡 Points
Seeing both an agonist and an antagonist come out of one imidazoquinoline family, steered by stereochemistry, is a good argument for making both enantiomers early. For an adjuvant or autoimmune program, that switch is useful, but reporter-cell data alone only gets it to a hit; cytokine profiling in primary cells would tell me whether it holds up.