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.

28 Dec 2023·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of Orally Available and Brain Penetrant AEP Inhibitors

Q1 · MEDICINE

Article

Author: Hewings, David S ; Heer, Dominik ; Brändlin, Mathis ; Müller, Lutz ; Kuhn, Bernd ; Beurier, Angélica ; Mesch, Stefanie ; He, Weiping ; Joedicke, Lisa ; Pinard, Emmanuel ; Westwood, Paul ; Schuler, Angelika ; Manevski, Nenad ; Gloria, Ludivine Esteves ; Brom, Virginie ; Kaniyappan, Senthilvelrajan ; Baumann, Karlheinz ; Marty, Christine ; Rothe, Judith ; Krummenacher, Daniela ; Tosstorff, Andreas ; Hochstrasser, Remo ; Kronenberger, Alexandra ; Gutbier, Simon ; Rudolph, Markus G ; Grüninger, Fiona ; Bartels, Björn ; Sivasothy, Thulase ; Morandi, Federica ; Schnider, Christian

Alzheimer's Disease (AD) is the most widespread form of dementia, with one of the pathological hallmarks being the formation of neurofibrillary tangles (NFTs). These tangles consist of phosphorylated Tau fragments. Asparagine endopeptidase (AEP) is a key Tau cleaving enzyme that generates aggregation-prone Tau fragments. Inhibition of AEP to reduce the level of toxic Tau fragment formation could represent a promising therapeutic strategy. Here, we report the first orthosteric, selective, orally bioavailable, and brain penetrant inhibitors with an irreversible binding mode. We outline the development of the series starting from reversible molecules and demonstrate the link between inhibition of AEP and reduction of Tau N368 fragment both in vitro and in vivo.

08 Nov 2023·JCI Insight

Cholestanol accelerates α-synuclein aggregation and spreading by activating asparagine endopeptidase

Article

Author: Zhang, Zhentao ; Ye, Keqiang ; Zhang, Zhaohui ; Guo, Jifeng ; Tang, Beisha ; Liu, Miao ; Bu, Lihong ; Yu, Ting ; Chen, Liam ; Niu, Xuan ; Jiang, Haiqiang ; Feng, Hongyan ; He, Juanfeng ; Nie, Shuke

Cerebrotendinous xanthomatosis (CTX), an autosomal recessive disorder characterized by high levels of cholestanol in the blood and accumulation of cholestanol in multiple tissues, especially the brain, often presents in parkinsonism. However, it remains unknown whether cholestanol plays a role in the pathogenesis of sporadic Parkinson's disease (PD). Here, we show that the levels of serum cholestanol in patients with sporadic PD are higher than those in control participants. Cholestanol activates the protease asparagine endopeptidase (AEP) and induces the fragmentation of α-synuclein (α-syn) and facilitates its aggregation. Furthermore, cholestanol promotes the spreading of α-syn pathology in a mouse model induced by intrastriatal injection of α-syn fibrils. KO of AEP or administration of an AEP inhibitor ameliorates α-syn pathology, degeneration of the nigrostriatal dopaminergic pathway, and PD-like motor symptoms. These results not only indicate that cholestanol contributes to the aggregation and spreading of α-syn by activating AEP but also reveal an opportunity for treating PD with AEP inhibitors.

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Preclinical	China	Shenzhen Boruijian Pharmaceutical Co., Ltd.	30 Apr 2024
Amyotrophic Lateral Sclerosis	Preclinical	China	Shenzhen Boruijian Pharmaceutical Co., Ltd.	30 Apr 2024
Parkinson Disease	Preclinical	China	Shenzhen Boruijian Pharmaceutical Co., Ltd.	30 Apr 2024

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