This article provides a systematic review of protein-, peptide-, and nucleic acid-based targeted protein degradation (TPD) technologies, with a focus on their advantages in addressing 'undruggable' targets and the challenges associated with delivery, offering comprehensive guidance for the development of next-generation degraders.
Literature Overview
The article 'Protein-Based Degraders: From Chemical Biology Tools to Neo-Therapeutics,' published in the journal Chemical Reviews, reviews and summarizes the current state of development in targeted protein degradation (TPD) technologies based on biological macromolecules such as proteins, peptides, and nucleic acids. The article systematically elaborates on the advantages of these 'biological drugs' as targeting modules in overcoming the limitations of traditional small-molecule degraders, including their ability to target intrinsically disordered proteins, transmembrane proteins, and extracellular proteins. Meanwhile, the authors provide a detailed introduction to display technologies and computational design methods for identifying protein binders, analyze the mechanisms of different degradation pathways (ubiquitin-proteasome system, lysosome, and autophagy pathways), and discuss delivery strategies and future directions for biological degraders. The entire section is coherent and logically structured, ending with a Chinese period.Background Knowledge
Targeted protein degradation (TPD) is a groundbreaking strategy in the field of biopharmaceuticals that aims to eliminate disease-causing proteins through the cell's natural degradation systems, rather than merely inhibiting their activity as traditional drugs do. PROTACs and molecular glues have shown great potential, but their reliance on small-molecule ligands binding to 'druggable' pockets limits their application to a large number of 'undruggable' targets that lack well-defined binding sites. Many disease-related proteins, such as transcription factors, scaffold proteins, and highly disordered proteins, are thus difficult to target with traditional degraders. Protein-based degraders (bioPROTACs) utilize antibodies, nanobodies, peptides, or non-IgG scaffold proteins as targeting modules, enabling recognition of conformational epitopes on protein surfaces, thereby expanding the range of degradable proteins. Furthermore, by linking lysosome-targeting receptors or autophagy-related signals, these degraders can also clear membrane and secreted proteins. However, poor cellular permeability, low in vivo stability, and potential immunogenicity of biological macromolecules remain major obstacles to clinical translation. Against this backdrop, this article comprehensively reviews the design principles, screening methods, mechanisms of action, and delivery strategies of bioPROTACs, providing a systematic reference for advancing this emerging therapeutic modality.
Research Methods and Experiments
This article employs a literature review methodology to systematically summarize and evaluate key recent advances in the field of protein-based degraders. The authors first define categories of 'biological drugs' as targeting modules, including peptides, antibody fragments, and non-IgG scaffold proteins, and compare their physicochemical properties and binding characteristics. Subsequently, major technological platforms for discovering and optimizing protein binders are introduced in detail, such as phage display, yeast display, cell-free display, and computational-aided design including generative artificial intelligence approaches. The article further categorizes and elaborates on three intracellular pathways through which bioPROTACs mediate protein degradation: the ubiquitin-proteasome system (via Cullin-dependent or non-dependent E3 ligases), the endosome-lysosome pathway (via lysosome-targeting receptors or sorting signals), and the autophagy-lysosome pathway. For each mechanism, the authors list representative molecular designs and experimental evidence. In the delivery section, strategies to improve the cellular permeability of biological macromolecules are systematically discussed, including protein engineering, peptide carriers, bacterial systems, and nanostructure injection, with analysis of the stability, circulation time, specificity, and future prospects of different delivery systems.Key Conclusions and Perspectives
Research Significance and Prospects
This review provides an important theoretical framework and practical guide for developing next-generation protein degradation therapies. It not only systematically summarizes existing technological platforms but also highlights key challenges in the field, such as delivery efficiency and immunogenicity control. With advances in protein engineering and delivery technologies, bioPROTACs are expected to become powerful new tools for treating complex diseases such as cancer, neurodegenerative disorders, and autoimmune diseases.
Future research should focus on developing more efficient cell-penetrating strategies, optimizing pharmacokinetic properties, and exploring the design of multispecific degraders. Additionally, integrating single-cell analysis and in vivo screening technologies will help assess the real-world efficacy and safety of bioPROTACs in physiological environments.
Conclusion
This article provides a comprehensive review of the current status and prospects of protein-based degraders (bioPROTACs) as an emerging therapeutic strategy. Compared to traditional degradation technologies that rely on small-molecule ligands, bioPROTACs utilize peptides, antibodies, or non-IgG scaffold proteins as targeting modules, enabling recognition of conformational epitopes on protein surfaces, thereby expanding the scope of degradable targets—particularly demonstrating unique advantages for 'undruggable' targets such as intrinsically disordered domains, transmembrane regions, and extracellular proteins. The article systematically elaborates on binder screening methods, including display technologies and computational design, and provides a detailed comparison of the molecular mechanisms of different degradation pathways, such as ubiquitin-proteasome, lysosomal, and autophagy pathways. Although bioPROTACs show promise in targeting flexibility and specificity, their clinical translation remains limited by intracellular delivery efficiency, in vivo stability, and potential immunogenicity. Future efforts must combine advanced delivery systems with protein engineering approaches to propel this field forward from chemical biology tools toward true 'neo-therapeutics.' This review offers researchers a systematic knowledge framework and holds significant guiding value for advancing innovation in targeted protein degradation technologies.
