Scientists posting in the journal Nature Chemical Biology have identified a new class of compounds, referred to as “pharmacologic chaperones,” which could help in a totally new approach to how Alzheimer’s disease is handled.
The group describes that a so-called retromer protein complex performs an essential part in neurons by steering away amyloid precursor protein (APP) from a portion of the cell where it is divided, developing amyloid-beta – a possibly toxic byproduct considered as a hallmark of Alzheimer’s.
This study lead by Dr. Scott Small, the team made use of computer-based virtual testing to determine the new “chaperone” substances.
They say these substances can significantly maximize retromer levels and reduce amyloid-beta levels in hippocampal neurons, and Dr. Small states that their strategy “may show to be safer and more efficient than conventional therapies for neurologic disease, which generally target single proteins.”
He and his group formerly revealed that, in the brains of sufferers with Alzheimer’s disease, retromer is lacking, and they exhibited how decreasing retromer levels in cultured neurons increased amyloid-beta levels, and vice versa.
They afterwards went on to show this impact in animals, monitoring that these modifications lead to symptoms associated to Alzheimer’s.
After a conversation at a scientific meeting, Dr. Small and team considered whether they could simply avoid retromer from degrading and assist its function.
“The idea that it would be effective to secure a protein’s structure is one that nature identified a long back ago. We just understand how to do that pharmacologically,” claims Prof. Gregory A. Petsko.
He notes that other researchers had previously determined the 3D structure of retromer, so for them, the difficult task was to discover tiny molecules that were capable to “bind to retromer’s weak point and strengthen the whole protein complex.”
To obtain this, the team tested identified chemical compounds making use of virtual simulations, to theorize how the compounds could link with the retromer protein complex. Via this novel procedure, they recognized 100 potential candidates that could strengthen retromer, and they observe that 24 of them revealed promise.
One in specific, known as R55, considerably enhanced retromer’s stability, even when it was exposed to a heat stress test.
Leaving comments on their study, Dr. Small states that:
“Our results recognize a new class of pharmacologic agents that are developed to treat neurologic disease by focusing on a defect in cell biology, instead of a defect in molecular biology.”