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Chemists are inventing molecular scalpels to clean up unwanted proteins from cell surfaces



Chemists are inventing molecular scalpels to clean up unwanted proteins from cell surfaces

EGFR, a protein important in promoting cancer, is shown in purple here, decorating the cell surface (left). After EGFR-targeted LYTAC treatment, all EGFR protein is aggregated into lysosomes, degradation compartments in the cell (right). Credit: Steven Banik

When scientists find a potentially dangerous protein on a cell, they could imagine them shrinking to become little surgeons, cutting out only the problematic molecule, and leaving healthy parts of the cell intact. While deft hands and sharp instruments would never be able to cut a single protein from the cell surface, according to a study published in the publication nature July 29.

Stanford chemists have developed a new class of molecules that transport unwanted proteins from the cell surface or environment into the lysosome, a cell compartment dedicated to protein degradation. These molecules, called lysosome-targeted chimeras or LYTACs, function by selectively labeling a protein with a label that conceals its fate for the disposal of cell debris. This selective degradation could help researchers study and treat diseases such as cancer and Alzheimer̵

7;s disease, the causes of which are related to surface proteins.

“It’s like a molecular scalpel,” said lead author Steven Banik, a postdoctoral fellow in the laboratory Carolyn Bertozzi, professors Anne T. and Robert M. Bass at the Faculty of Humanities and Sciences. “This tool makes it possible to accelerate the natural degradation of a single protein between all the different proteins that are on or off the cell.”

Proteins are vital for many biological processes, such as metabolism and intercellular communication, but some can also help with diseases such as the spread of cancer and avoid immune regulation. Traditional methods that prevent these bad actors include the use of drugs that block the active site of the protein, where other cellular components can dock while the protein works on them, usually by moving atoms around. However, this blocking strategy is imperfect; sometimes the binding bag is too shallow and the inhibitor is released too quickly. At other times, the activity of a protein is derived from its physical properties, such as its stiffness, and not from any active site, so that blocking a small portion of the entire protein is insufficient. In these cases, the only option is to delete the protein cell.

Protein degradation as a therapeutic strategy has been particularly popular since the development of PROTAC or chimera-focused proteolysis 20 years ago. PROTACs, which search for and label intracellular proteins for degradation, have been successful in research laboratories and initial clinical studies, but rely on a degradation pathway that is inaccessible to about 40 percent of all proteins that sit on top or outside the cell membrane. , Bertozzi and Banik did not accept that certain proteins – and diseases – would be out of reach.

“My lab has always been interested in what’s going on on the cell surface, which contains all these proteins important for immune modulation,” said Bertozzi, who is also a co-founder of the Baker family at Stanford ChEM-H. “We have identified many surface and secreted proteins that we believe play pathogenic roles in cancer, and LYTACs could 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 adapted to bind to any protein of interest. On the other hand, there is a short amino acid sequence or peptide with a sugar called mannose-6-phosphate.

This sugar serves as an accounting sticker for the cell. When a cell makes proteins that belong to the lysosome, it attaches to these sugars to ensure that they reach their destination. “Mannose-6-phosphate behaves like a zip code,” Banik said. “These sugars tell the cell: ‘I’m taking this protein to the lysosome. Please send it to me. “” There are receptors on the cell surface that interact with this sugar coating, and when they catch the LYTAC molecule and coat it, when the cells get into the cell, they are drawn in with it.

By attaching this tag to proteins, LYTACs carry the mechanism of natural cell Shuttling designed to accompany newly synthesized lysosomal proteins into their new home. But while lysosomal proteins are resistant enough to survive the degradative enzymes they encounter in the lysosome, most proteins are not, so those labeled by LYTAC are usually destroyed.

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

“With protein degradation strategies, you can not only expand what is drugs, but also improve therapies that already exist,” 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. ”


Cell protein shredders to fight cancer


More information:
Steven M. Banik et al. Chimeras targeting lysosomes to degrade extracellular proteins, nature (2020). DOI: 10,1038 / s41586-020-2545-9

Provided by Stanford University



Citations: Chemists exchange molecular scalpels to purify unwanted proteins from cell surfaces (2020, July 30), obtained on July 31, 2020 from https://phys.org/news/2020-07-chemists-craft-molecular-scalpels-unwanted. html

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