Small molecule inhibitors of asparagine endopeptidase for the treatment of neurological disorders.
- Nontoxic and specific inhibitors selectively block asparagine endopeptidase (AEP), leaving other related cysteine proteases unaffected.
- Alzheimer’s candidate is blood-brain barrier permeable.
Nearly 36 million people worldwide have Alzheimer’s disease or a related dementia and that number is expected to rise as life expectancy and overall population continues to increase in the United States and around the world. Asparagine endopeptidase (AEP) is implicated in various human disorders including cancers and neurodegenerative diseases. AEP is upregulated in aged normal brain and human Alzheimer’s disease (AD) brain. Several inhibitors of AEP have been described; however, they are all peptide-based, subject to proteolytic degradation and tend to exhibit low bioavailability. An effective small molecule inhibitor of AEP has yet to be identified and current therapeutics only treat symptoms and/or delay disease progression.
Emory inventors have identified small-molecule inhibitors of asparagine endopeptidase (AEP). The lead compounds are cell permeable with low cytotoxicity and highly selective for AEP, reducing reactivity to other cysteine proteases. Chronic treatment of 5xFAD and TauP301S mice with oral administration of one lead compound ameliorates synapse loss and augments long-term potentiation (LTP), resulting in lower memory loss. This compound also exhibits high blood-brain barrier permeability. This lead compound is a great candidate to treat neurological disorders including Alzheimer’s disease. Another compound was shown to inhibit breast cancer cell migration.
Lead compounds have been characterized for their pharmacokinetics and toxicity and tested in mouse models.