Grassystatin-derived peptides selectively inhibit cathepsin E and have low affinity to cathepsin D

Microglial cathepsin E plays a role in neuroinflammation and amyloid β production in Alzheimer’s disease

“…Accordingly, peptides that specifically inhibit CatE appear to be particularly important in clarifying its functions. Stotz et al, modified grassystatin-derived peptides that provided a useful approach for us to interfere with CatE enzymatic activity in the brains of AD mice (Stotz et al, 2020). In our experiments, cannulation-delivered GV elicited functional improvement in AD mice, which exhibited increased cognitive function, reduced neuroinflammation, and reduced Aβ accumulation compared with the ACSF group.…”

“…Specific inhibition of CatE without affecting highly abundant CatD was only possible using a protease inhibitor protein from Ascaris suum, but grassystatin peptides from marine cyanobacteria were more recently identified as potent inhibitors of this enzyme (Kwan et al, 2009). Simplified grassystatin variants (GV) have been reported to selectively inhibit CatE, and there is some indication of inhibition of CatD and napsin A (NapsA) (Stotz et al, 2020). The failure of therapies based on administration of peptides via intravenous or oral routes is often due to their inability to cross the blood-brain barrier (BBB), therefore, we chose direct cannulation for delivery of GV into mouse brains (Figure 6a).…”

“…In familial amyloidotic polyneuropathy (FAP), CatE was reported as a novel FAP biomarker and a possible modulator for innate immune cell chemotaxis to the disease affected tissues (Goncalves et al, 2017). Yet little is known about the role of CatE in AD, and CatE specific inhibitor is unavailable until grassystatin-derived peptides were modified (Stotz et al, 2020).…”