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Author Spotlight: Evaluating Biophysical Assays for Characterizing PROTACS Ternary Complexes
Published on: January 12, 2024
The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination
Jinmei Jin1, Ye Wu1, Jinjiao Chen1,2
1Institute of Interdisciplinary Integrative Medicine Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Abstract:
Despite dramatic advances in drug discovery over the decades, effective therapeutic strategies for cancers treatment are still in urgent demands. PROteolysis TArgeting Chimera (PROTAC), a novel therapeutic modality, has been vigorously promoted in preclinical and clinical applications. Unlike small molecule PROTAC, peptide PROTAC (p-PROTAC) with advantages of high specificity and low toxicity, while avoiding the limitations of shallow binding pockets through large interacting surfaces, provides promising substitutions for E3 ubiquitin ligase complex-mediated ubiquitination of "undruggable proteins". It is worth noting that successful applications of p-PROTAC still have some obstacles, including low stability and poor membrane permeability. Hence, we highlight that p-PROTAC combined with cell-penetrating peptides, constrained conformation technique, and targeted delivery systems could be the future efforts for potential translational research.
Insights
Peptide PROTACs (p-PROTACs) offer a promising approach for cancer treatment, targeting undruggable proteins with high specificity and low toxicity. Overcoming stability and permeability challenges through advanced techniques will enable their translation to clinical applications.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Cancer therapeutics urgently require novel strategies beyond current drug discovery advancements.
- PROteolysis TArgeting Chimeras (PROTACs) are emerging as a potent therapeutic modality in preclinical and clinical settings.
- Peptide PROTACs (p-PROTACs) present advantages over small molecule PROTACs, including high specificity, low toxicity, and the ability to target proteins with large binding surfaces, addressing limitations of traditional drug design.
Purpose of the Study:
- To review the potential of peptide PROTACs (p-PROTACs) as a therapeutic strategy for cancer treatment.
- To highlight the advantages of p-PROTACs in targeting previously undruggable proteins via E3 ubiquitin ligase complex-mediated ubiquitination.
- To identify and discuss the key challenges hindering the clinical translation of p-PROTACs.
Main Methods:
- Review of existing literature on PROTAC technology and peptide-based therapeutics.
- Analysis of the mechanisms underlying p-PROTAC action, including specificity and toxicity profiles.
- Exploration of strategies to overcome limitations such as low stability and poor membrane permeability.
Main Results:
- p-PROTACs demonstrate high specificity and low toxicity, offering a viable alternative to small molecule PROTACs.
- p-PROTACs can effectively target 'undruggable proteins' by leveraging large interacting surfaces for E3 ligase recruitment.
- Significant obstacles remain, primarily concerning the inherent instability and poor cell membrane penetration of p-PROTACs.
Conclusions:
- p-PROTACs hold considerable promise for cancer therapy, particularly for targeting challenging proteins.
- Future research should focus on enhancing p-PROTAC stability and cell permeability.
- Combining p-PROTACs with cell-penetrating peptides, conformational constraint techniques, and targeted delivery systems represents a promising avenue for translational research.
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