When targeting harmful proteins that cause or spread disease, drugs usually block the protein’s active site, making it unable to function and causing severe damage. New strategies targeting these proteins may send them into different types of cellular protein degradation mechanisms, such as lysosomes, which function like protein shredders in the cell.
In a new study, researchers from Stanford University in the United States have revealed how one pathway to cellular lysosomes works. In the process, they have opened the door to new therapies for age-related diseases, autoimmune diseases, and treatment-resistant cancers. These findings could also improve treatments for lysosomal storage diseases, which are rare but often severe and mainly affect infants and children. The results of the study were published on October 20, 2023, in the journal Science under the title “Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras”.
The co-corresponding author of the paper, Professor Carolyn Bertozzi from the School of Humanities and Sciences at Stanford University, stated, “Accurately understanding how proteins are transported to lysosomes for degradation can help us harness the inherent power of cells to eliminate proteins that cause significant harm to the human body. This new research clearly elucidates a typically opaque intracellular process, shedding light on a potentially groundbreaking new world for drug discovery.”
Preventing Uncontrolled Proteins
Proteins are typically beneficial to the body, assisting in processes such as food digestion or repairing torn muscles. However, they can also have destructive effects. For instance, in cancer, proteins may become part of a tumor and/or promote its uncontrolled growth. They can contribute to devastating diseases like Alzheimer’s and accumulate in the heart, affecting the pumping of blood to other parts of the body.
To halt the actions of destructive proteins, drugs can be used to block the active sites of proteins, preventing their interaction with cells—a standard approach in decades of research. Twenty years ago, proteolysis targeting chimeras (PROTACs) emerged, capable of interacting with harmful proteins within cells and delivering them to lysosomes for degradation.
Currently undergoing clinical trials, PROTACs have demonstrated efficacy in treating cancer. However, they can only target 60% of intracellular proteins. In 2020, researchers at Stanford University’s ChEM-H introduced a new method through Lysosome Targeting Chimeras (LYTACs), which can target the remaining 40% of proteins. LYTACs can identify and label proteins on the cell periphery or cell membrane surface for subsequent degradation.
These discoveries have opened up a new class of research and therapeutic approaches, but the precise mechanism of this process remains unclear. It has also been observed that predicting when LYTACs will be successful or when they may fall short of expected results is challenging.
New Therapeutic Target
In this recent study, the first author of the paper, Green Ahn, utilized CRISPR gene screening technology to identify and describe how LYTAC regulates the cellular components involved in protein degradation. Through this screening, the authors discovered a connection between the levels of neddylation of cullin 3 (CUL3), a protein that plays a key role in the process of cellular protein degradation, and the efficacy of LYTAC. The exact nature of this connection is not yet clear, but the authors found that the more neddylated CUL3 present, the better the efficacy of LYTAC.
Measuring the levels of neddylated CUL3 can determine which patients are more likely to respond to LYTAC therapy. Bertozzi stated that this was a surprising discovery, as previous research had not indicated such a correlation.
They also identified proteins that hinder the action of LYTAC. LYTAC functions by binding to certain receptors outside the cell, using these receptors to transport harmful proteins into lysosomes for degradation. However, they found that proteins with mannose 6-phosphate (M6P) occupy these receptors, preventing LYTAC from binding. By disrupting the biosynthesis of M6P, the number of unoccupied receptors on the cell surface increases, allowing LYTACs to potentially hijack these receptors.
New Biology, a Novel Approach to Treating Diseases
In addition to aiding in the development of more effective therapeutic drugs based on LYTACs, these findings also offer new and more efficient treatment approaches for lysosomal storage disorders. Lysosomal storage disorders are genetic diseases in which the lysosomes in the human body lack a sufficient or appropriate amount of enzymes to function normally. This can lead to the toxic accumulation of fats, sugars, and other harmful substances, impacting the overall health of the body.
These discoveries not only contribute to the development of LYTACs as more effective therapeutic drugs but also present new and more efficient treatment methods for lysosomal storage disorders, which are genetic diseases where insufficient or inappropriate enzymes in the human lysosomes prevent them from functioning properly. This can result in the toxic accumulation of fats, sugars, and other harmful substances, leading to damage to the heart, brain, skin, and bones. Enzyme replacement therapy is a common treatment method that utilizes a pathway similar to LYTAC to enter lysosomes and enable their function. Understanding the mechanism and rationale behind LYTAC’s action may lead to more effective delivery of these enzymes.
The authors liken this research to the crucial discovery of how thalidomide works. Thalidomide was initially a prescription drug used in the 1950s to treat morning sickness in pregnant women, primarily in the UK, but was withdrawn from the market in 1961 due to its association with severe birth defects. However, in the 1990s, it was found to be an effective treatment for multiple myeloma. In 2010, the mechanism by which it acts through protein degradation was understood, significantly advancing the field of PROTAC research.