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http://hdl.handle.net/2445/210183
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DC Field | Value | Language |
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dc.contributor.advisor | Fabriàs Domingo, Gemma | - |
dc.contributor.author | Alqahtani, Abdulateef | - |
dc.contributor.other | Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació | - |
dc.date.accessioned | 2024-04-19T08:40:36Z | - |
dc.date.issued | 2023-10-25 | - |
dc.identifier.uri | http://hdl.handle.net/2445/210183 | - |
dc.description.abstract | [eng] In 2001, the initial hypothesis of targeted protein degradation (TPD) was born to announce the launching of a new era of therapeutics development not by inhibiting a component of ubiquitin-proteasome system as small molecule inhibitors, but by recruiting the whole system to induce the degradation of specific proteins. TPD techniques can efficiently target long-lived proteins since they are not constrained by protein turnover, thus overcoming some of the drawbacks of UPS inhibitors. The majority of these technologies also share the advantageous pharmacokinetic characteristics of small compounds resembling drugs. Importantly, due to their various modes of action, they may expand the conventional druggable space. Many technologies with the therapeutic potential of targeting protein for degradation have been under massive study and development including PROteolysis TArgeting Chimeras (PROTACs). PROTAC is a strategy that utilizes the UPS to target a specific protein and induces its degradation by employing hetero-bifunctional molecules consisting of a ligand to bind the protein of interest (POI), another ligand to recruit an E3 Ub ligase and a linker to bind the two ligands. These molecules interact simultaneously and hijack the enzymatic machinery by forming a ternary complex (POI:PROTAC:E3 ligase) that facilitates the transfer of Ub moieties and the formation of polyubiquitin chain(s) on the target protein. The polyubiquitinated protein will be recognized and promoted to degradation by the proteasome. PROTACs bind specific targets and E3 Ub-ligases, promoting ubiquitination and degradation of targets by the proteasome. Multiple chimeras that degrade proteins relevant in several diseases have been developed, and the number is quickly increasing, indicating their therapeutic projection. Given some limitations of E3- based PROTACs such as the diversity and complexity of E3 ligases, alternative strategies in target protein degradation are pursued. The main objective of this thesis was to develop a novel type of chimeras with the capacity to induce the degradation of different proteins by direct signaling to the 26S proteasome by interacting with USP14, a 26S-associated deubiquitinating enzyme involved in substrate processing and allosteric regulation of 26S activity. The overall results obtained in the biological studies provide proof of concept for this 26S-directed PROTAC, which should expand the potential of target protein degradation. Although this novel approach lacks the limitations associated to ubiquitination in the classical E3-protacs (i. e. different tissue or cell types' expression patterns of targeted E3, inadequate levels of Ub and/or Ub signaling factors under stressful circumstances), the formation of ineffective ternary complexes threatening the effectiveness of classical E3-based PROTACs is not circumvented by USP14- directed PROTACS. The linker is one of the factors that may lead to weak ternary complexes. Until very recently, linker design and selection was a "trial and error" endeavor. However, future avenues for rational linker design, including advances in computational methods, will accelerate the identification of optimized PROTACs. | ca |
dc.description.abstract | [spa] Los PROTAC se unen a objetivos específicos y a las Ub-ligasas E3, promoviendo la ubiquitinación y degradación de objetivos por parte del proteosoma. Se han desarrollado múltiples quimeras que degradan proteínas relevantes en varias enfermedades, y el número está aumentando rápidamente, lo que indica su proyección terapéutica. Dadas algunas limitaciones de los PROTAC basados en E3, como la diversidad y complejidad de las ligasas E3, se buscan estrategias alternativas en la degradación de proteínas objetivo. El principal objetivo de esta tesis fue desarrollar un nuevo tipo de quimeras con capacidad de inducir la degradación de diferentes proteínas mediante señalización directa al proteosoma 26S a partir de la interacción con USP14, una enzima desubiquitinante asociada a 26S implicada en el procesamiento de sustratos y la regulación alostérica de Actividad 26S. Los resultados generales obtenidos en los estudios biológicos proporcionan una prueba de concepto para este PROTAC dirigido por 26S, que debería ampliar el potencial de degradación de las proteínas objetivo. Aunque esta nueva aproximación carece de las limitaciones asociadas a la ubiquitinación en los PROTACs E3 clásicos (es decir, patrones de expresión de E3 dirigido a diferentes tejidos o tipos de células, niveles inadecuados de Ub y/o factores de señalización de Ub bajo circunstancias estres), La formación de complejos ternarios ineficaces que amenazan la eficacia de los PROTAC clásicos basados en E3 no se evita con los PROTACs dirigidos por USP14. El vinculador es uno de los factores que pueden conducir a complejos ternarios débiles. Hasta hace muy poco, el diseño y la selección de estos enlazadores era una tarea de "prueba y error". Sin embargo, las vías futuras para el diseño de vinculadores racionales, incluidos los avances en los métodos computacionales, acelerarán la identificación de PROTACs optimizados. | ca |
dc.format.extent | 209 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | ca |
dc.publisher | Universitat de Barcelona | - |
dc.rights | (c) Alqahtani, Abdulateef, 2024 | - |
dc.source | Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentació | - |
dc.subject.classification | Química farmacèutica | - |
dc.subject.classification | Desenvolupament de medicaments | - |
dc.subject.classification | Desnaturalització de proteïnes | - |
dc.subject.classification | Proteòmica | - |
dc.subject.other | Pharmaceutical chemistry | - |
dc.subject.other | Drug development | - |
dc.subject.other | Protein denaturation | - |
dc.subject.other | Proteomics | - |
dc.title | Design, synthesis and biological evaluation of novel molecules with the capacity of inducing the degradation of different proteins by direct signaling to the proteasome | ca |
dc.type | info:eu-repo/semantics/doctoralThesis | ca |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.rights.accessRights | info:eu-repo/semantics/embargoedAccess | ca |
dc.embargo.lift | 2024-10-25 | - |
dc.date.embargoEndDate | info:eu-repo/date/embargoEnd/2024-10-25 | ca |
dc.identifier.tdx | http://hdl.handle.net/10803/690655 | - |
Appears in Collections: | Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentació |
Files in This Item:
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AA_PhD_THESIS.pdf | 8.92 MB | Adobe PDF | View/Open Request a copy |
Document embargat fins el
25-10-2024
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