New Way To Hit Alzheimer’s Target: Caspase-6 Inhibitor

An agent that inhibits the protease enzyme caspase-6 in a totally new way could help lead to a novel type of medication for Alzheimer’s disease, a condition in which caspase-6 may play a key role.

Drug researchers in academia and the pharmaceutical industry have been actively pursuing inhibitors of caspase-6 and other caspases as potential Alzheimer’s medications for several years. But inhibitors against caspases have been found to cause serious side effects, and none has passed clinical trials.

The problem is that the active sites of caspases are very similar to one another. So agents targeting one of the various enzymes’ active sites tend to hit off-target caspase active sites as well, causing liver toxicity and other side effects.

Now, scientist and lab head Rami N. Hannoush of Genentech, in South San Francisco, and coworkers report having screened libraries of peptides on surfaces of bacteriophage viruses to identify a peptide called pep419 that inhibits caspase-6 by a novel mechanism (Nat. Chem. Biol., DOI: 10.1038/nchembio.967).

It works a little like glue. It binds to an allosteric site on an inactive precursor of caspase-6, inducing the precursor to form tetramers. This precursor already tends to form dimers, so only two molecules of pep419 are needed to cause each tetramer to form. Pep419-induced tetramer formation ties up the precursor, discouraging it from maturing to the active form and expressing normal enzymatic activity.

Peptides don’t necessarily make for the best drugs, but similar small molecules might lead to effective and selective caspase-6 inhibitors, the researchers say.

“Inhibiting caspase-6 with a drug like pep419 might halt Alzheimer’s disease progression before people even have symptoms,” says Alzheimer’s expert Andrea LeBlanc of McGill University, in Montreal. Her group discovered over the past decade that caspase-6 seems to play an important role in Alzheimer’s at a very early stage of the disease. She says the Genentech study “shows there is hope” in developing a new type of caspase-6-based Alzheimer’s medication. “The importance of this paper is the identification of a new site that can stabilize and inhibit this enzyme.”

Neuroscientist Bart De Strooper, who specializes in Alzheimer’s and Parkinson’s disease mechanisms at the University of Leuven, in Belgium, says the study “demonstrates an interesting approach to develop caspase-6-specific inhibitors. Over the years, considerable circumstantial evidence has implicated caspases, and more specifically caspase-6, in Alzheimer’s disease. It remains a challenge to provide direct proof for this claim, but highly specific inhibitors, active in vivo and with little off-target toxicity, are the tools needed to make progress along that path.”

Guy Salvesen, a protease specialist at Sanford-Burnham Medical Research Institute, in La Jolla, Calif., who has consulted for Genentech, comments that “the challenge will be to convert pep419 into some kind of pharmacologically reasonable small molecule.” Pep419’s selectivity “is not quite all the way there yet, but it provides an avenue toward very high selectivities that cannot be achieved by the active-site-directed approaches of conventional inhibitors.”