Podcast Summary
New drugs that degrade problematic proteins: Scientists have developed a new type of drug molecule that can target and degrade problematic proteins in the body, offering a potential solution for diseases caused by their presence or misplacement.
Key takeaway from this episode of Journal Club is that scientists are developing a new type of drug molecule that can degrade problematic proteins in the body, offering a potential solution for diseases caused by the presence or misplacement of these proteins. The paper discussed in this episode, published in Nature, introduces a new class of drugs called lysosome targeting chimeras. These drugs work by delivering a protein complex to the lysosome, the cell's recycling center, where it breaks down the target protein. The senior author of the paper, Carolyn Bertozzi, explains that this approach is exciting because it allows for the targeting of proteins that have been previously inaccessible to conventional drugs. The new drug molecule has the potential to reduce the levels of problematic proteins or remove them from the wrong place or wrong time. The discussion also touches upon the difference between conventional drugs, which work by binding to a target and blocking its function, and the new drug class, which uses a different mechanism to degrade the target protein.
Targeting proteins for degradation with PROTACs: PROTACs are a new class of drugs that bridge proteins and ubiquitin machinery for targeted degradation, expanding the druggable proteome and offering potential for treating various diseases.
PROTACs represent a new class of drugs that expand the druggable proteome by targeting proteins for degradation rather than blocking their activity. This approach, pioneered by Craig Cruz from Yale and Ray Deshaies from Caltech, leverages the cell's natural ubiquitin proteasome system to mark and destroy specific proteins. Unlike traditional drugs that bind to enzymes or pockets to inhibit their function, PROTACs act as a bridge between the target protein and the ubiquitin machinery, enabling the addition of ubiquitin tags and subsequent degradation. This method opens up the possibility of targeting proteins that are not easily drugged through inhibition, making it a promising approach for treating various diseases. However, it's important to note that these techniques only target intracellular proteins, leaving the vast world of extracellular proteins untouched. The field has expanded beyond PROTACs to include other types of protein degraders, but the potential for targeting a broader range of proteins through degradation is a significant advancement.
New drug modality PROTACs can't target 40% of human proteins, but LITACs, a type of degrader, might for extracellular and cell surface proteins.: PROTACs and LITACs are different drug modalities with PROTACs unable to target large extracellular and cell surface proteins, but LITACs, a type of degrader, may effectively eliminate these proteins for more potent therapeutic effects.
PROTACs, a new drug modality, have the potential to target intracellular proteins effectively, but they cannot be used to target the large portion of extracellular and cell surface proteins, which make up about 40% of the human proteome. These proteins are important for drug development, especially for targets contributing to cancer. While some of these proteins can be targeted with monoclonal antibodies, a degradation strategy using LITACs (lysosome targeting chimera) might lead to more potent effects at lower doses. The advantage of degraders is their ability to reduce the level of the target protein continuously, and potentially target multiple drugs to one protein, leading to deeper inhibitory effects. This has been observed in some early human clinical studies with PROTACs. Although LITACs are still in their infancy, the rationale behind their potential effectiveness is based on their ability to eliminate the target protein rather than just blocking its activity. This could lead to more significant therapeutic effects.
New drug LiTAP targets and degrades extracellular proteins using the endosome lysosome pathway: Researchers have developed a new drug called LiTAP that uses the natural cellular process of the endosome lysosome pathway to extract and degrade extracellular proteins. This targeted approach could have implications for cancer treatment and other therapeutic areas.
Researchers have developed a new type of drug called LiTAP (Lysosomal Targeting Antibody Complexes) to degrade extracellular and membrane-associated proteins. They do this by using the endosome lysosome pathway, a natural cellular process for degrading extracellular molecules. LiTAP consists of two parts: one part binds the target protein, and the other part binds a lysosomal trafficking receptor. This allows the target protein to be extracted from the extracellular space and degraded inside the cell. The researchers have identified several known receptors in human biology that can be hijacked to pull in and degrade extracellular proteins. One of these receptors is the mannose 6 phosphate receptor, which can be used to target proteins with mannose 6 phosphate groups attached. To ensure specificity, the researchers use high affinity, high specificity antibodies against their target of interest, which are already approved human medicines. For example, they have developed a LiTAP targeting the epidermal growth factor receptor (EGFR) using the human drug cetuximab. This approach allows for targeted degradation of specific proteins, which could have implications for cancer treatment and other therapeutic areas.
New Lysosomal Targeting Chimeric (LITEC) Molecules for Protein Degradation: Researchers developed LITEC molecules, antibodies with added glycans, to shuttle specific proteins into the lysosome for degradation, potentially providing more effective on-target effects and eliminating proteins entirely.
Researchers have developed a new type of therapeutic agent called a lysosomal targeting chimeric (LITEC) molecule, which is an antibody with added glycan molecules that help it shuttle specific proteins into the lysosome for degradation. This not only blocks the protein's function but also eliminates it entirely, potentially making it more effective than traditional inhibitors. Additionally, the complexity of biology is being better understood, and proteins often have multiple functions that can interact with other proteins. Degrading a protein entirely can impact its entire network of interactions, which may lead to more profound on-target effects, although there is a risk of off-target effects depending on how the line between on and off target is drawn. This research opens up new opportunities for treating diseases that involve the accumulation of misfolded or unfolded proteins in the extracellular environment, such as amyloid diseases, for which there are currently no effective treatments.
Approach to Addressing Diseases with Limited Treatment Options: The LIHTC approach, which uses a ligand to pull out and degrade pathogenic proteins or molecules, shows promise for diseases where standard treatments are limited, including light chain amyloidosis, diseases associated with mucins, and fibrosis. The technology is being optimized to improve binding and degradation processes.
The LIHTC (Ligand-Independent Targeted Degradation of Amyloid-forming Proteins) approach, which involves using a ligand to pull pathogenic proteins or molecules out of their environment and degrade them, shows promise in addressing diseases where the standard treatment options are limited. This includes conditions like light chain amyloidosis, where the pathogenic molecules don't have an enzymatic function, and diseases associated with mucins, a type of transmembrane glycoprotein, where the function of the molecule is physical rather than biochemical. Additionally, the approach could be useful in fibrosis, where the goal is to degrade collagen scarring. The LIHTC technology, which is currently in its second and third generation of improvements, aims to optimize the structures to turn them into therapeutics. This includes enhancing the ligand's ability to bind to the target protein and improving the degradation process itself. Overall, the LIHTC approach offers a unique solution for addressing diseases where traditional drug discovery methods have been unsuccessful due to the nature of the pathogenic molecules or systems.
Expanding Targeted Protein Degradation Beyond Intracellular Targets with Second-Generation LITACs: Second-generation LITACs with site-specific conjugations can effectively target specific mannose 6 phosphate receptors, expanding potential for addressing conditions like liver fibrosis. LITACs can now be engineered from various binders, opening up a broader universe of potential degraders.
The field of targeted protein degradation is expanding beyond intracellular targets with the development of second-generation LITACs. These new LITACs have site-specific conjugations and can be engineered to target specific mannose 6 phosphate receptors, making them more effective and specific for certain tissues or cell types. For instance, the new generation of LITACs targets the liver-specific a sialoglycoprotein receptor, which is crucial for addressing conditions like liver fibrosis. Additionally, LITACs can now be developed from various binders, including small molecules, expanding the potential targets for this approach. This opens up a broader universe of potential degraders and could lead to significant advancements in the field.
