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Pharmacists cut molecular scales to remove unwanted proteins from cell surfaces



Pharmacists cut molecular scales to remove unwanted proteins from cell surfaces

EGFR, an important protein to help cancer grow, shown here in purple, decorates the cell surface (left). After treatment with LYTAC targeting EGFR, all EGFR protein is turned into lysosomes, the degradation compartments in the cell (right). Credit: Steven Banik

When scientists find a potentially dangerous protein on a cell, they can imagine that they will fail themselves to become tiny surgeons, tear up the problematic molecule and leave the healthy parts of the cell intact. While strong hands and sharp instruments will never be able to capture a single protein from a cell surface, a new molecular tool could make cell surgery easier, according to a study published in Nature on 29 July.

Stanford chemists have developed a new class of molecules that move unwanted proteins from the surface or surrounding environment of a cell to the lysosome, the cell compartment dedicated to protein degradation. These molecules, called chimera-targeting lysosomes, or LYTACs, work by selectively labeling a labeled protein that seals its fate for cellular garbage disposal. This selective degradation can help researchers study and treat diseases such as cancer and Alzheimer’s, whose causes are linked to facial proteins.

“It’s like a molecular scalpel,” said lead author Steven Banik, a postdoc in the lab of Carolyn Bertozzi, Professor Anne T. and Robert M. Bass at the School of Humanities and Sciences. “This tool allows to accelerate the natural degradation of a single individual protein among all the different proteins contained inside or outside a cell.”

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Proteins are vital to many biological processes such as metabolism and intercellular communication, but some can also help diseases such as cancer spread and evade immune regulation. Traditional methods of inhibiting these malignancies involve the use of drugs that block the active site of the protein, where other cellular components may shrink as the protein builds up, usually by walking on the protein. atoms. But this blocking strategy is imperfect; sometimes the binding pocket is too low and the inhibitor releases too quickly. Other times, the activity of a protein comes from its physical properties, such as its hardness, and not from any active site, so blocking a small portion of all protein is not enough. In these cases, draining the protein cell is the only option.

Protein degradation as a therapeutic strategy has been especially popular since the development of PROTACs, or 20 years ago the target of proteolysis. PROTACs, which look for and label intracellular proteins for degradation, have seen success in research laboratories and in early clinical studies, but rely on a pathway of degradation that is inaccessible to about 40 percent of all proteins that rely on or outside the cell membrane. . Bertozzi and Banik did not accept that certain proteins – and diseases – would not be met.

“My lab has always been interested in what’s going on in the cell surface, which contains all these proteins important for immune modulation,” said Bertozzi, who is also the Co-Director of the Baker Family of Stanford ChEM-H. “We’ve identified many surface proteins and secretions that we think are playing pathogenic roles in cancer, and LYTACs can help us better understand and explore them as drug targets.”

The key to making the tool work is its bifunctional design. One side of this molecule can be specially designed to bind to any protein of interest. On the other side is a short sequence of an amino acid, or peptide, studded with a sugar called mannose-6-phosphate.

This sugar serves as a bookkeeping label for the cell. When the cell builds proteins that are part of the lysosome, it attacks these sugars to make sure they arrive at their destination. “Mannose-6-phosphate acts like a zip code,” Banik said. “These sugars tell the cell, ‘I’m taking this protein to the lysosome. Please send me there.'” There are receptors on the cell surface that interact with this sugar coating, and when they hold a LYTAC molecule and pull it into the cell, the tagged proteins are dragged along with it.

By attaching this label to proteins, LYTACs hijack a natural cellular shuttling mechanism designed to escort newly synthesized lysosomal proteins to their new home. But since lysosomal proteins are tough enough to survive the degrading enzymes encountered in the lysosome, most of the proteins are not, so those labeled with the LYTAC method are generally destroyed.

Stanford researchers show that, in cells, they can target and degrade important proteins in Alzheimer’s disease and cancer. According to them, the protein binding end of LYTAC can be anything that binds to a protein, such as an existing antibody or drug, so in the future, many proteins and other diseases can be attacked.

“With protein degradation strategies, you can not only expand what is weakened but also improve the therapies that are already there,” Bertozzi said. “Every cell has lysosomes. Every cell already has a way to degrade proteins. No matter what your goal is, if you can get LYTAC there, you can degrade it.”


Cellular protein peels to fight cancer


More information:
Steven M. Banik et al. Lysome-targeting chimeras for the degradation of extracellular proteins, Nature (2020). DOI: 10.1038 / s41586-020-2545-9

Provided by Stanford University



Citation: Pharmacists craft molecular scales to remove unwanted proteins from cell surfaces (2020, July 30) retrieved July 31, 2020 from https://phys.org/news/2020-07-chemists -craft-molecular-scalpels-unwanted.html

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