Inhibiting caspase-6 by stabilizing an inactive form

A peptide that inactivates caspase-6, a cell death promoting enzyme important in Alzheimer’s disease, is reported this week in Nature Chemical Biology.

Caspases are enzymes that mediate cell death and inflammatory responses. Although many caspase inhibitors have been reported, there are currently no drugs available that target these enzymes. Most drug discovery approaches aimed at this target class have produced compounds that inhibit the active site of the enzymes through an irreversible modification. Translation of this approach to the clinic has been hindered because long-term exposure to these compounds is associated with liver toxicity, thus new approaches to inhibit these enzymes are needed.

Rami Hannoush and colleagues report on a peptide called pep419 that inhibits caspase-6 by a new mechanism, providing a potential new strategy to inhibit this enzyme. Upon activation in cells, caspase-6 is processed from an inactive to an active form. Pep419 binds to and stabilizes an inactive form of caspase-6, selectively inhibiting caspase-6 activity in neuronal cells. These results indicate that recapitulating the activity of pep419 could be an effective drug discovery strategy for targeting caspase-6.