▎WuXi AppTec Content Team Editor
When Dr. Carmela Sidrauski came to the lab of Lasker Prize-winning Professor Peter Walter at UCSF At the time, she didn’t think about finding a “magic medicine”. While conducting automated screening experiments, a compound that was excluded caught her interest. She moved it to a drug worthy of continued research because its activity was “stunning.”
The potential use of this molecule sounds unbelievable these days, but since Carmela decided to keep studying it, scientific experiments have shown that it can not only restore memory in brain-damaged mice It also shows potential in the treatment of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS, also known as ALS). In addition, it reduced ageing-related cognitive decline and, in healthy mice, gave them the ability to “remember”. What makes it so widely used?
Image source: 123RF
Wonder Molecules from the “Trash Can”
In Professor Walter’s view, this may be because it involves a fundamental mechanism for maintaining cellular health. This mechanism is called the unfolded protein response. Simply put, the unfolded protein response is a quality control system for cells in the process of making proteins. When it finds that there are too many unfolded proteins in the cell, it activates two signaling pathways, one One signaling pathway reduces gene expression and reduces protein production, and another signaling pathway increases the ability of proteins to fold. This process helps balance the capacity of the endoplasmic reticulum (ER) to fold proteins and the amount of protein produced, so that there is enough ER in the cell to complete the folding of nascent proteins.
However, if the ER in the cell is insufficient to complete protein folding due to disease or other reasons, a large amount of unfolded protein accumulates in the ER. When the ER is “overwhelmed”, the unfolded protein response can lead to cell death, which is associated with a variety of diseases. In patients with type 2 diabetes, for example, the constant demand for insulin may cause islet beta cells to die in response to unfolded proteins. In neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, the unfolded protein response can also kill nerve cells as protein aggregates accumulate.
Screenshot source: Lasker Foundation official website
Professor Walter received the Lasker Prize for Basic Medical Research in 2014 for his work on unfolded protein responses, and in 2018 he was awarded the “Oscar of Science” for scientific breakthroughs Award (Breakthrough Prize). In his view, the unfolded protein response is an “unexplored gold mine” that helps the brain repair damaged memory pathways. If this response can be controlled, it may be possible to repair the cellular mechanisms that are disrupted in diseased cells. If you can repair the diseased cells, you can heal the patient.
But the regulation of the unfolded protein response is intricate. Where are the key nodes that can regulate the response? To this end, Professor Walter collaborated with UCSF’s Small Molecule Discovery Center to use high-throughput screening to examine the effects of more than 100,000 compounds on the unfolded protein response. Carmela, a postdoc in the lab, is in charge of the project.
One day, while Carmela was examining data on drugs that had been eliminated by automated screening, a molecule caught her eye. The molecule, which was far more potent than others, was eliminated because subsequent tests showed it might not be soluble enough to be a potential drug.
“That’s not a reason to throw it away.” She thought, “It’s very potent!” She decided to take a gamble and bought a larger amount of the compound for follow-up research.
Subsequent research found thatthis molecule can not only restart the cell protein synthesis that the stress factor aborted, but even more amazingly, this effect is effective for almost all stress factors.
Enhancing memory
And protein synthesis plays an important role in the formation of long-term memory. For a long time, scientific research has shown that the memory of the brain is stored in a network of different nerve cells, and protein synthesis is crucial for regulating the synapses that transmit information between nerve cells. If the level of protein synthesis is reduced, it will affect the formation of long-term memory. One consequence of stress response is to reduce the level of protein synthesis, so if preventing this consequence of stress response, can it play a role in enhancing memory?
Professor Walter’s lab, together with partners at McGill University, tested the compound, called ISRIB, in mice. They found that when the compound was injected into mice, it quickly crossed the blood-brain barrier and showed no toxicity. And ISRIB-injected mice were able to quickly remember the location of the platform hidden under the water in the maze test, finding the platform 3 times faster than the control group. This means the compound has memory-enhancing properties.
This result has attracted the attention of Silicon Valley investors after the publication. In 2015, Calico, a life sciences company founded by Google’s parent company Alphabet, announced that it had acquired the rights to develop this compound. This is a company led by Dr. Arthur D. Levinson, former Chairman and CEO of Genentech, that uses advanced technology to advance the biological understanding of aging and longevity. Carmela also joined Calico as the company’s interim head of research and development, continuing to lead the development of this project.
Image source: Calico’s official website
Currently, ABBV-CLS-7262, an investigational therapy based on ISRIB, has entered clinical development for the treatment of amyotrophic lateral sclerosis. Calico has partnered with AbbVie to jointly develop the therapy.
Rejuvenate an aging brain
Professor Walter’s team, together with partners, then tested the compound’s effects in aging mice. Cognitive decline is very common as people age. We all know that neurodegenerative diseases such as Alzheimer’s disease can significantly reduce the cognitive level of the elderly. Even in healthy older adults, however, cognitive and memory skills, as well as the ability to perform daily activities, decline. With the aging of the world’s population, how to make people live longer and have a healthier future is an urgent problem that needs to be solved.