Caspase1

Tethering with extenders was also used to identify inhibitors to the anti-inflammatory target caspase-1 [28, 29]. In this case, one of the same extenders previously designed for caspase-3 selected an entirely different set of fragments. This is consistent with different substrate peptide sequence preferences: WEHD for caspase-1 vs DEVD for caspase-3 [30].

As with caspase-3, these hits were converted into potent, soluble inhibitors by replacing the disulfide linkage with a simple alkyl linkage (Fig. 9.10). As in the case of caspase-3, rigidifying the linker could improve affinity, as could introducing a hydrophobic moiety at the S2 position. Several of these molecules demonstrated activity in cellular assays and selectivity for caspase-1 over the closely related caspase-5. Crystallography of several of these molecules in complex with caspase-1 revealed that they bind in an extended conformation as expected, but that the S2 pocket that collapses in caspase-3 remains open in caspase-1.

Was this article helpful?

0 0
Cure Tennis Elbow Without Surgery

Cure Tennis Elbow Without Surgery

Everything you wanted to know about. How To Cure Tennis Elbow. Are you an athlete who suffers from tennis elbow? Contrary to popular opinion, most people who suffer from tennis elbow do not even play tennis. They get this condition, which is a torn tendon in the elbow, from the strain of using the same motions with the arm, repeatedly. If you have tennis elbow, you understand how the pain can disrupt your day.

Get My Free Ebook


Post a comment