Researchers publishing in the journal Nature Chemical Biology have described a new class of compounds, called "pharmacologic chaperones," which could aid in a completely new approach to how Alzheimer's disease is treated.
The team explains that a so-called retromer protein complex plays an important part in neurons by steering away amyloid precursor protein (APP) from a part of the cell where it is split, creating amyloid-beta - a potentially toxic byproduct regarded as a hallmark of Alzheimer's.
Led by Dr. Scott Small, director of the Alzheimer's Disease Center at Columbia University Medical Center in New York, the team used computer-based virtual screening to identify the new "chaperone" compounds.
They say these compounds can greatly increase retromer levels and decrease amyloid-beta levels in hippocampal neurons, and Dr. Small says their approach "may prove to be safer and more effective than conventional treatments for neurologic disease, which typically target single proteins."
He and his team previously showed that, in the brains of patients with Alzheimer's disease, retromer is deficient, and they demonstrated how reducing retromer levels in cultured neurons raised amyloid-beta levels, and vice versa.
They later went on to show this effect in animals, observing that these changes led to symptoms related to Alzheimer's.
Virtual simulations helped researchers with compounds
After a discussion at a scientific meeting, Dr. Small and colleagues wondered whether they could easily prevent retromer from degrading and support its function.
The researchers say their "chaperone" compounds show promise in increasing retromer levels and decreasing amyloid-beta levels in hippocampal neurons.
"The idea that it would be beneficial to protect a protein's structure is one that nature figured out a long time ago. We're just learning how to do that pharmacologically," says Prof. Gregory A. Petsko, from Brandeis University in Massachusetts.
He notes that other scientists had already identified the 3D structure of retromer, so for them, the challenge was to find tiny molecules that were able to "bind to retromer's weak point and stabilize the whole protein complex."
To achieve this, the team screened known chemical compounds using virtual simulations, to theorize how the compounds could connect with the retromer protein complex.
Through this novel process, they identified 100 potential candidates that could stabilize retromer, and they note that 24 of them showed promise.
One in particular, called R55, significantly increased retromer's stability, even when it was subjected to a heat stress test.
Commenting on their research, Dr. Small says:
"Our findings identify a novel class of pharmacologic agents that are designed to treat neurologic disease by targeting a defect in cell biology, rather than a defect in molecular biology."
Team is now testing compound's clinical effects in mouse models
Next, the team assessed how R55 affected neurons in the hippocampus, the brain region involved in learning and memory. The researchers were concerned the compound would be toxic, but after further investigation using mouse neurons in cell culture, they found it to be "relatively non-toxic."
Additionally, a further experiment revealed that R55 greatly increased retromer levels and decreased amyloid-beta levels in cultured neurons of both healthy mice and those of an Alzheimer's mouse model.
Because of this success, the team is now testing clinical effects of the compound in the mouse model.
"The odds that this particular compound will pan out are low," says Prof. Petsko, "but the paper provides a proof of principle for the efficacy of retromer pharmacologic chaperones."
Speaking with Medical News Today, Dr. Small explained that the team is also developing chemical analogs, as well as testing R55:
Dr. Small went on to explain that a lead compound is one that has the required properties to become a safe, effective drug. "But the hit can be used as a scaffold, from which other compounds can be generated and tested for efficacy and safety," he explained.
"In drug discovery, a first 'hit' (in our case R55) simply provides proof-of-principle that the 'target' is valid. In this case, targeting endosomal transport defects that have been implicated in the causes of [Alzheimer's disease and Parkinson's disease]. It is unlikely that a first hit will become the lead compound."