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.
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.
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).
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.
|European Patent Office||Published Application||2019/169183||09/06/2019||2018-200|
Additional Patent Pending
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