Journal Club: Degrading Drugs for Problematic Proteins
Sep 24, 2020
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Stanford Professor Carolyn Bertozzi discusses the development of drugs called LYTACs that can degrade disease-causing proteins. The conversation covers the engineering of these drugs, their benefits, and future optimization. They explore the concept of proteolysis targeting chimeras as an alternative to traditional drugs and the potential therapeutic applications of lytac technology. The episode also discusses advancements in drug design, optimizing lie tech for therapeutics, and the potential of targeted protein degradation for improving patient outcomes.
Lysosome Targeting Chimeras (Lytacs) offer a promising alternative for drug development by degrading disease-causing proteins and targeting a class of proteins previously difficult to treat with traditional drugs.
Protacs and Lytacs, two types of drugs discussed in the podcast, expand the range of druggable targets by facilitating protein degradation and targeting proteins that do not have a suitable pocket for traditional drug binding.
Deep dives
New Type of Drug to Degrade Proteins
The podcast discusses a recent scientific article published in Nature that introduces a new type of drug called Lysosome Targeting Chimeras. These drugs aim to degrade disease-causing proteins by reducing their levels or removing them from specific areas. This approach is particularly exciting because it targets a class of proteins that have been previously difficult to treat with traditional drugs. By artificially bridging the gap between target proteins and the ubiquitin machinery in cells, these drugs facilitate protein degradation, offering a promising alternative for drug development.
Expanding the Drugable Proteome
The podcast explores the concept of proteolysis targeting chimeras (protacs) and how they differ from conventional drugs. Protacs were developed to shut down pathogenic proteins by targeting them for degradation instead of simply blocking their function. This approach has expanded the drugable proteome because protacs can target proteins that do not have a suitable pocket for traditional drug binding. In addition to protacs, the podcast introduces lysosome targeting chimeras (Lytacs) as a similar but earlier-stage technology. Lytacs utilize the cell's endosome-lysosome pathway to degrade membrane-associated and extracellular proteins, further expanding the range of druggable targets.
The Potential of Lysosome Targeting Chimeras
The podcast highlights the potential of lysosome targeting chimeras (Lytacs) in drug development. Lytacs show promise in targeting extracellular proteins, such as those involved in amyloid diseases and difficult-to-treat cancers. By redirecting these proteins to the lysosome for degradation, Lytacs offer a new approach to combatting diseases that have been challenging to treat with traditional drugs. Ongoing research aims to optimize Lytac design, including improving the structure and exploring different lysosomal trafficking receptors for increased specificity. Overall, the podcast emphasizes how targeted protein degradation, particularly through Lytacs, opens up new possibilities for developing effective therapies.
In Bio Eats World's Journal Club episodes, we discuss groundbreaking research articles, why they matter, what new opportunities they present, and how to take these findings from paper to practice. In this episode, Stanford Professor Carolyn Bertozzi and host Lauren Richardson discuss the article "Lysosome-targeting chimaeras for degradation of extracellular proteins" by Steven M. Banik, Kayvon Pedram, Simon Wisnovsky, Green Ahn, Nicholas M. Riley & Carolyn R. Bertozzi, published in Nature584, 291–297 (2020).
Many diseases are caused by proteins that have gone haywire in some fashion. There could be too much of the protein, it could be mutated, or it could be present in the wrong place or time. So how do you get rid of these problematic proteins? Dr. Bertozzi and her lab developed a class of drugs -- or modality -- that in essence, tosses the disease-related proteins into the cellular trash can. While there are other drugs that work through targeted protein degradation, the drugs created by the Bertozzi team (called LYTACs) are able to attack a set of critical proteins, some of which have never been touched by any kind of drug before. Our conversation covers how they engineered these new drugs, their benefits, and how they can be further optimized and specialized in the future.
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