Amyloid Precursor Protein-Selective BACE Inhibitors for Alzheimer’s Disease

Tech ID: 29441 / UC Case 2018-200-0

Summary

UCLA researchers in the Department of Neurology have invented novel Alzheimer’s disease (AD) therapeutics that are selective for BACE1 inhibition and cleavage of the amyloid precursor protein (APP) substrate.

Background

Alzheimer’s disease is characterized by the formation of amyloid plaques in the brain, largely comprised of amyloid-β (Aβ) peptides. These Aβ peptides are generated by the sequential cleavage of full-length APP by BACE1 (β-site APP cleaving enzyme). The use of BACE inhibitors to stop this process has been a focus for AD therapeutics since it is the first and rate-limiting step in Aβ production. However, direct inhibition of BACE1 is associated with off-target effects, such as inhibiting non-BACE1 enzymes or the cleavage of non-APP substrates.

Innovation

UCLA researchers led by Professor Varghese John have developed a novel class of APP-selective BACE inhibitors (ASBIs) that are selective for both the enzyme BACE1 and the full-length APP substrate. These AD therapeutics showed low inhibition of other enzymes (e.g., cathepsin D) and little inhibitory activity in cleavage of other substrates (e.g., neuregulin-1 or p-selectin glycoprotein ligand 1). Additionally, these BACE1 inhibitor therapeutics are permeable across the blood brain barrier (BBB).

Applications

  • Alzheimer’s and Parkinson’s disease 
  • Proteopathic diseases 
  • Prion diseases

Advantages

  • Selective to BACE1 enzyme and APP substrate 
  • Dose-response inhibition of BACE activity 
  • Permeable across the BBB

State Of Development

Several novel ASBI-based therapeutics have been synthesized and tested. Preliminary in vivo studies in mice and rats have been accomplished. Additional small-molecule ASBIs will be synthesized and tested in the future.

Patent Status

Country Type Number Dated Case
Patent Cooperation Treaty Published Application 2019169183 09/06/2019 2018-200
 

Additional Patent Pending

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Inventors

  • John, Varghese

Other Information

Keywords

Alzheimer’s disease, AD, Parkinson’s disease, prion, prion disorders, proteopathic diseases, proteopathy, therapeutics, small-molecule, BACE, BACE1 inhibitors, APP-selective BACE inhibitors, ASBI, amyloid-ß peptides, Aß peptides, amyloid precursor protein, APP substrate, blood brain barrier, BBB

Categorized As