Introduction
Targeted Protein Degradation (TPD) has become a revolutionary way to work for the treatment of many diseases, yet they have been very successful in the treatment of diseases that have been identified as these methods of small-molecule inhibitors. Most small-molecule inhibitors react by binding to active regions of proteins, shutting them off. This approach is weak in many instances because it fails to deal with proteins with clear active sites or if they look as “undruggable.” For this reason, proteolysis-targeting chimeras (PROTACs) have become one of the first therapeutic techniques allowing the selective degradation of target proteins while providing new opportunities for drug discovery.
The Future of Protein Degrader Technology: An Emerging Overview
Protein degraders are one of the great advances in drugs that have come to be produced. They are specifically made using the cell’s natural ubiquitin-proteasome system to selectively degrade disease-associated proteins. By utilizing a unique mechanism, the ubiquitin-proteasome pathway, a protein degrader not only blocks the functioning of a protein but actually kills it from the cellular world. Unlike traditional inhibitors, PROTEIN DEGRADERS do not simply stop protein function; they target the protein and kill it, eliminating it from the cell. This revolutionary process can also be used to target many diseases, including those difficult to control with traditional therapies.
Protein degraders came from Craig Crews and colleagues in 2001. The basic principle of the protein degraders technique is that it exploits the cell’s own machinery for protein degradation to remove certain proteins that influence disease progression.
The Mechanism of Protein Degraders
The protein degrader structure is simple and efficient. One protein degrader molecule is composed of two functional groups linked by a linker: one of them binds the target protein (POI), and the other recruits an E3 ubiquitin ligase. After the protein degrader molecule binds to the POI, the E3 ligase tags the POI with ubiquitin and marks its degradation by the proteasome. It is highly specific and efficient, so you can selectively remove targets from the cells and remove other cells.
The specificity of the protein degrader is ascribed to the binding affinity of the POI-binding group and the E3 ligase-recruiting group. The linker is the main mediator for these two groups, which can impact the pharmacokinetic performance of the protein degrader molecules in general. The design of the right linker is one of the greatest challenges in protein degrader evolution since it must accommodate correct orientation and localization of the POI and E3 ligase to achieve successful ubiquitination.
Fig. 1 Properties of interest and computational approaches in TPD.1
The Development of Protein Degraders
Protein degraders have come a long way in the past two decades. Scientists have worked extremely hard to know what mechanisms are involved in protein degradation and to develop better-designed protein degrader molecules. Researchers have gained a better understanding of the mechanism that processes protein degradation and have developed advanced molecules like protein degraders, which have shown promising results in both preclinical trials and, increasingly, in clinical trials.
One of the major challenges in protein degrader design is optimizing pharmacokinetic properties. Protein degraders are often more complex and larger than most small-molecule drugs, and their solubility, permeability, and stability can vary from product to product. However, recent advancements in medicine and formulation science have enabled the development of protein degraders with better drug-like properties, making them more suited for in vitro applications.
Another key field of study has to be discovering new E3 ligases and POI-binding groups. The diversity of existing ligands can extend the number of target proteins that can be degraded by protein degraders, potentially creating new therapeutic opportunities. Additionally, ongoing research aims to increase the efficiency and selectivity of protein degraders and reduce the impact and toxicity that goes into off-target areas.
Creative Biolabs’ Support of Protein Degrader Research
Creative Biolabs is actively supporting protein degrader research, including the development of molecular degraders in countries like the Netherlands, Canada, and the UK.
Creative Biolabs has been an early-stage researcher in protein degrader technology, providing a range of services and products to help develop this revolutionary approach. We work on protein degraders from the development and production of molecules to their efficacy and specificity in degrading target proteins.
1. Design and Synthesis: Our expert chemists and biologists work with clients to develop protein degrader molecules for their specific research. Our understanding of protein structure and function was used to construct molecules that incorporated E3 ligases and attached to the protein being used. We have all kinds of building blocks and linkers to enable the customization of protein degraders for diverse targets and applications.
2. Tests for Efficacy and Specificity: After the protein has been synthesized, we use an array of advanced assays to evaluate its adequacy and specificity. These include cell-based degradation assays, Western blot analysis, and mass spectrometry-based proteomics for the quantitative determination of target protein degradation and its impact on cellular function. Our complete testing processes make researchers more effective at protein degrader designs and choose the most effective ones for further development.
3. Preclinical Development: We provide preclinical development services like pharmacokinetic and pharmacodynamic studies to optimize the properties of protein degrader molecules for in vivo applications. Our objective is to ensure that the protein degrader molecules not only efficiently cleave the target protein but also exhibit favorable drug-like properties (solubility, permeability, stability). We work closely with clients to develop and implement preclinical studies that provide critical insights into the safety and effectiveness of protein degraders to lead to successful clinical applications.
4. Customized Services: Every research project is unique, so Creative Biolabs offers customized solutions that best fit our customers. Whether you require a standard protein degrader or a highly specialized molecule, we provide the flexibility to meet diverse research needs. We also offer consultation options that will help scientists handle protein degrader development problems and make the best decision during drug discovery.
How the Future of Protein Degrader Technology Could Change Our Society
Protein degrader technology has immense potential. With the growing comprehension of the ubiquitin-proteasome interaction model, we will see more innovative use cases of protein degraders in treating many diseases.
One area of particular interest is the development of protein degraders for cancer. A number of cancer-related proteins cannot be addressed with other inhibitors; protein degraders provide a logical solution by targeting these proteins and inhibiting their oncogenic activity. Also in neurodegenerative diseases like Alzheimer’s and Parkinson’s, there are some studies on protein degraders to prevent the progression of these diseases, where misfolded proteins are the primary drivers of disease development.
The addition of protein degraders to other therapeutic interventions, like immunotherapy and gene therapy, is also promising. Protein degraders can improve the results of these treatments by altering the proteins that regulate immune responses or expression of genes.
Conclusion
Protein degrader technology is a new frontier in drug discovery, offering a specialized system that identifies previously uncharted proteins and provides new possibilities for improving the treatment of invasive diseases. Creative Biolabs is dedicated to advancing this field through our cutting-edge research and development services. We believe protein degrader technology will become a part of the medical world, and we are excited to be part of this revolution.
As we move forward, we also expect that protein degrader technology will continue to evolve, with ongoing research and development unlocking its full therapeutic potential. At Creative Biolabs, we strive to remain at the forefront of this booming technology so that scientific researchers get the tools and expertise they need to exploit the true potential of protein degraders.
Call to Action
Researchers and scientists are encouraged to contact us and ask them to get a better idea of what protein degraders can offer and why we offer it. Whether you are developing a protein degrader molecule or in the preclinical planning stages, Creative Biolabs has the skills and expertise to support your efforts. Reach out to us today and learn how we can help you harness the power of protein degrader technology to advance your drug discovery. Together, we can push the boundaries of current medicine and offer new hope to patients worldwide.
Reference:
- Barmak Mostofian, Holli-Joi Martin, et al.Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods. Journal of Chemical Information and Modeling. 2023 63 (17), 5408-5432.
- Distributed under Open Access license CC BY 4.0, without modification.