Biotechnologists have developed a drug candidate that blocks production of diseasecausing neurotoxins in mouse models
Reducing the concentration of cathepsin B using an enzyme inhibitor prevents the creation of the neurotoxic peptide, pyroglutamate-AB (pGlu-AB), which has been linked to the development of Alzheimer’s disease (AD). The candidate inhibitor drug, a cysteine protease inhibitor named E64d, was developed by scientists from the University of California, San Diego School of Medicine, the Medical University of South Carolina and San Diego-based American Life Science Pharmaceuticals, and has already been shown to be safe in humans. Now research using mouse models of AD has been reported in the Journal of Alzheimer’s Disease (vol.1, page 1, 2014).
Current AD drugs treat some symptoms of the devastating neurological disorder, but none actually slow its progress, prevent or cure it. No new AD drug has been approved in more than a decade. “No other therapeutic program is investigating cysteine protease inhibitors for treating AD,” said Vivian Hook, the paper’s lead author. The researchers focused on cathepsin B production of N-truncated pGlu-AB, a peptide or short chain of amino acids, and the blockade of cathepsin B by E64d, a compound shown to inhibit cysteine proteases, a type of enzyme.
AD is characterized by accumulation of a variety of AB peptides as oligomers (twisted tangles of protein) and amyloid plaques (abnormal clusters of protein fragments) in the brain. These are factors involved in neuronal loss and memory deficits over time. The neurotoxic AB peptides are created when enzymes cleave a large protein called amyloid precursor protein (APP) into smaller AB peptides of varying toxicity. N-truncated pGlu-Av has been shown to be among the most neurotoxic of multiple forms of Av peptides.
Much AD research has focused on the APP-cutting enzyme BACE1 B-secretase, but its role in producing pGlu-Av was unknown. Cathepsin B is an alternative B-secretase. It cleaves the wild-type B-secretase site of APP, which is expressed in the major sporadic and many familial forms of AD. Hook and colleagues looked at what happened after gene knockout of BACE1 or cathepsin B. They found that cathepsin B, but not BACE1, produced the highly toxic pGlu-Av.
The scientists found that E64d, an enzyme inhibitor of cathepsin B, reduced production of pGlu-AB and other AD-associated AB peptides. Key was the finding that E64d and cathepsin B gene knock out resulted in improved memory deficits in a mouse model of AD. “This is an exciting finding,” said Hook. “It addresses a new target – cathepsin B – and an effective, safe small molecule, E64d, to reduce the pGlu-AB that initiates development of the disease’s neurotoxicity. No other work in the field has addressed protease inhibition for reducing pGlu-ABof AD.”
E64d has already been shown to be safe in clinical trials of patients with muscular dystrophy and would, therefore, likely prove safe for treating AD as well. Hook hopes to launch Phase 1 human clinical trials in the near future with a modified version of the drug candidate.