Development of asparagine endopeptidase inhibitors for treating neurodegenerative diseases

Asparagine endopeptidase (AEP), or legumain, is a cysteine protease implicated in various disorders, including atherosclerosis, cancers, neurodegenerative diseases, and inflammation. The development of AEP inhibitors has emerged as a promising therapeutic strategy to modulate AEP activity and slow disease progression. Various AEP inhibitors have been explored, encompassing small molecules, peptide-based, antibody-based, and natural inhibitors. Substrate-mimetic and covalent inhibitors show significant potential for selectively targeting AEP's active site, whereas noncovalent inhibitors offer reversible modulation. Additionally, FDA-approved drugs have also garnered attention for their diverse structures and multitarget capabilities. In this review, we summarize advancements in AEP inhibitors, their mechanisms of action, therapeutic applications in neurodegenerative diseases, and the challenges in translating these findings into clinical practice.