Summary: Amyloid inhibitors, a type of Alzheimer’s drug under development, may not be as promising as once thought. A cheap and easy test early in the drug development process should help researchers focus on the most promising compounds. This finding does not apply to the vaccines being developed to clear amyloid.
If you’re one of the millions waiting for Alzheimer’s drugs now under development, you’ll want to know that researchers at the University of California, San Franciso (UCSF) have come to some interesting conclusions about one type of potential treatment. Which do you want first - the good news or the bad?
UCSF researchers Brian Shoichet, Ph. D. (left) and Robert Fletterick, Ph.D
Let’s start with the bad news. It looks like “amyloid inhibitors” may not be as promising as once thought. Some Alzheimer’s researchers are focused on developing these compounds to prevent beta amyloid proteins from clumping together to form the fibrils and plaques thought to be harmful to your brain. But as with other diseases, the trick is to find compounds that will affect only the beta amyloid “target,” without affecting other proteins your body and brain might need.
Research conducted in the lab of Brian Shoichet, a professor in the Department of Pharmaceutical Chemistry at UCSF, suggests that amyloid inhibitors often affect too many other proteins to be safe and effective Alzheimer’s treatments. The results of his work on this topic were published in late January in Nature Chemical Biology online.
Several years ago, Dr. Shoichet and his colleagues discovered that some compounds tend to inhibit a lot of different proteins. They do this by binding indiscriminately with all those proteins and forming big clumps, or aggregates. They labeled these compounds “promiscuous.”
More recently, they noticed that amyloid inhibitors being tested for Alzheimer’s looked a lot like the promiscuous compounds they had already identified. They tested three amyloid inhibitors (none of which are in human trials now) and found they behave in the same way other promiscuous compounds do. This suggests that they, too, are promiscuous, and so unlikely to target just beta amyloid. This finding does not apply to the vaccines being developed to clear amyloid.
Dr. Malcolm Leissring, an Alzheimer’s researcher and Assistant Professor at Mayo Clinic in Jacksonville, Florida, says that this is not good news for those hoping to develop amyloid inhibitors to treat Alzheimer’s. “Although widely pursued, amyloid inhibitors suffer from the fact that there must be at least a 1:1 relationship between the inhibitor and the amyloid, making it necessary to use very high concentrations,” he says. “This report suggests that the amount of amyloid inhibitor needed is probably even greater, perhaps at least a 10:1 or 100:1 ratio. The higher the concentration needed for efficacy, the higher the risks of side effects, so this does not augur well for this therapeutic approach.” Dr. Leissring was not involved in the UCSF study.
There’s more bad news: Dr. Shoichet believes that many substances that appear to inhibit tau [the protein in Alzheimer’s tangles] may also be “promiscuous.” “Compounds that inhibit tau through colloidal aggregation are almost certainly artifacts [meaning study results are misleading] and should be dropped,” he says.
It’s unclear how much this will affect drugs currently under development. Alzhemed, a drug that failed in clinical trials and is now being developed as a nutraceutical, is an amyloid inhibitor.
Dr. Shoichet and colleagues did not study Alzhemed, but they did test an antifungal drug called clioquinol. Their test results indicate that clioquinol may be promiscuous, and therefore not well-suited for Alzheimer’s treatment. Trials of clioquinol for Alzheimer’s have been inconclusive, but a second generation of that drug, PBT2, was developed by Prana Biotechnology and is currently in trial.
Now for the good news. First, some amyloid inhibitors are not promiscuous, according to Dr. Shoichet. “There are several beautiful examples of this, including Jeff Kelly’s work on ligands that bind to transthyretin and inhibit it,” he points out. “There is no doubt that these compounds are acting specifically.”
Second, the fact that clioquinol may be promiscuous does not necessarily mean that clioquinol, PBT2 or other amyloid inhibitors won’t be effective drugs. Dr. Shoichet says he thinks researchers and companies interested in clioquinol and PBT2 should investigate whether the two compounds are promiscuous, but he points out that they might work in ways other than aggregation. Dr. Leissring agrees. “Some of these compounds might have other effects that may explain why they have been shown to work in vivo,” he says. “For example, clioquinol has long been postulated to work by chelating zinc, which has been reported to accelerate the aggregation of beta amyloid. Recently, however, clioquinol was shown to work by a completely unexpected mechanism, namely by upregulating proteases that degrade beta amyloid.”
The third and final piece of good news is that it’s relatively cheap and easy to test to see whether compounds are “promiscuous” and thus likely to inhibit more than just beta amyloid. “Essentially, with any given compound, one can be pretty sure that it is a colloid-former [tends to form clumps that inhibit many proteins] in an afternoon or less,” says Dr. Shoichet. “For the majority it’s quite fast.”
In the long run, screening drug candidates for promiscuity early in the process should save time and money. “There is a lot of excellent research going on in this area, and our work will hopefully contribute in a small way by allowing investigators to focus on better candidates, rather than being distracted by artifacts,” Dr. Shoichet says.