Optimized M24B Aminopeptidase Inhibitors for CARD8 Inflammasome Activation

Inflammasomes are innate immune signaling platforms that
trigger
pyroptotic cell death. NLRP1 and CARD8 are related human inflammasomes
that detect similar danger signals, but NLRP1 has a higher activation
threshold and triggers a more inflammatory form of pyroptosis. Both
sense the accumulation of intracellular peptides with Xaa-Pro N-termini,
but Xaa-Pro peptides on their own without a second danger signal only
activate the CARD8 inflammasome. We recently reported that a dual
inhibitor of the Xaa-Pro-cleaving M24B aminopeptidases PEPD and XPNPEP1
called CQ31 selectively activates the CARD8 inflammasome by inducing
the build-up of Xaa-Pro peptides. Here, we performed structure–activity
relationship studies on CQ31 to develop the optimized dual PEPD/XPNPEP1
inhibitor CQ80 that more effectively induces CARD8 inflammasome activation.
We anticipate that CQ80 will become a valuable tool to study the basic
biology and therapeutic potential of selective CARD8 inflammasome
activation.