The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents
The induction of protein degradation in a highly selective and efficient way by means of druggable molecules is known as targeted protein degradation (TPD). TPD emerged in the literature as a revolutionary idea: a heterobifunctional chimera with the capacity of creating an interaction between a prot...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-12-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/24/5956 |
| _version_ | 1797544476660465664 |
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| author | Bernat Coll-Martínez Antonio Delgado Bernat Crosas |
| author_facet | Bernat Coll-Martínez Antonio Delgado Bernat Crosas |
| author_sort | Bernat Coll-Martínez |
| collection | DOAJ |
| description | The induction of protein degradation in a highly selective and efficient way by means of druggable molecules is known as targeted protein degradation (TPD). TPD emerged in the literature as a revolutionary idea: a heterobifunctional chimera with the capacity of creating an interaction between a protein of interest (POI) and a E3 ubiquitin ligase will induce a process of events in the POI, including ubiquitination, targeting to the proteasome, proteolysis and functional silencing, acting as a sort of degradative knockdown. With this programmed protein degradation, toxic and disease-causing proteins could be depleted from cells with potentially effective low drug doses. The proof-of-principle validation of this hypothesis in many studies has made the TPD strategy become a new attractive paradigm for the development of therapies for the treatment of multiple unmet diseases. Indeed, since the initial protacs (Proteolysis targeting chimeras) were posited in the 2000s, the TPD field has expanded extraordinarily, developing innovative chemistry and exploiting multiple degradation approaches. In this article, we review the breakthroughs and recent novel concepts in this highly active discipline. |
| first_indexed | 2024-03-10T14:02:04Z |
| format | Article |
| id | doaj.art-6b50055036844276bc9c072af9ed6121 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T14:02:04Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-6b50055036844276bc9c072af9ed61212023-11-21T01:04:36ZengMDPI AGMolecules1420-30492020-12-012524595610.3390/molecules25245956The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic AgentsBernat Coll-Martínez0Antonio Delgado1Bernat Crosas2Molecular Biology Institute of Barcelona (IBMB), Spanish National Research Council (CSIC), Barcelona Science Park, 08028 Barcelona, SpainResearch Unit on Bioactive Molecules (RUBAM), Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona, SpainMolecular Biology Institute of Barcelona (IBMB), Spanish National Research Council (CSIC), Barcelona Science Park, 08028 Barcelona, SpainThe induction of protein degradation in a highly selective and efficient way by means of druggable molecules is known as targeted protein degradation (TPD). TPD emerged in the literature as a revolutionary idea: a heterobifunctional chimera with the capacity of creating an interaction between a protein of interest (POI) and a E3 ubiquitin ligase will induce a process of events in the POI, including ubiquitination, targeting to the proteasome, proteolysis and functional silencing, acting as a sort of degradative knockdown. With this programmed protein degradation, toxic and disease-causing proteins could be depleted from cells with potentially effective low drug doses. The proof-of-principle validation of this hypothesis in many studies has made the TPD strategy become a new attractive paradigm for the development of therapies for the treatment of multiple unmet diseases. Indeed, since the initial protacs (Proteolysis targeting chimeras) were posited in the 2000s, the TPD field has expanded extraordinarily, developing innovative chemistry and exploiting multiple degradation approaches. In this article, we review the breakthroughs and recent novel concepts in this highly active discipline.https://www.mdpi.com/1420-3049/25/24/5956chimeraprotactargeted protein degradationubiquitinproteasomelysosome |
| spellingShingle | Bernat Coll-Martínez Antonio Delgado Bernat Crosas The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents Molecules chimera protac targeted protein degradation ubiquitin proteasome lysosome |
| title | The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents |
| title_full | The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents |
| title_fullStr | The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents |
| title_full_unstemmed | The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents |
| title_short | The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents |
| title_sort | potential of proteolytic chimeras as pharmacological tools and therapeutic agents |
| topic | chimera protac targeted protein degradation ubiquitin proteasome lysosome |
| url | https://www.mdpi.com/1420-3049/25/24/5956 |
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