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Author
Tarrats i Duran, Anna
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Abstract
The proteins found in living organisms are continuously degraded and synthetized through proteolytic and synthetic pathways. The proteolysis is an essential degradation system capable of controlling the degradation of misfolded proteins, which present translational errors or are damaged.
The ubiquitin-proteosome system (UPS) is one of several proteolytic pathways which present a great relevance in this work. UPS consists in the protein signaling, through an ubiquitination cascade regulated by a wide range of enzymes. When the protein is correctly signaled, it is lead to the 26S proteasome, which will take care of its degradation.
In the last decades, new technologies that allow a highly selective degradation of proteins have been developed under the name of targeted protein degradation, which include the so called PROteolysis TArgeting Chimeras (PROTACs). PROTACs are made up of a specific ligand for the protein of interest, another specific ligand for a selected E3 ligase and a linker. These heterobifunctional molecules act as adaptors that allow the binding of a specific protein to the ubiquitin-proteasome system through a ternary complex, with the aim to be signaled and subsequently degraded. This technology can be used in new therapeutic applications.
This work focuses on the synthesis of the spacers N3-PEG(3)-OH and N3-PEG(7)-OH from tetraethylene glycol, the ligand IU1-248 made from 4-(2,5-dimethyl-1H-pyrrol-1-yl) benzonitrile and, finally, an inactive analog od IU248 using ethyl acetoacetate as starting material.
The length of the spacers has a huge importance on the degradative effectiveness of the final product, since if the linker is too short, the formation of the ternary complex could be hampered by steric hindrance. On the other hand, if the spacer is excessively long, the protein-protein interactions necessary for the correct signaling through polyubiquitination would be hindered. Spacers of different lengths have been synthesized in order to study their effectiveness in different PROTACs.
The possibility of using a new type of PROTAC is currently being studied in our laboratories. This new PROTAC directs the protein of interest directly to the proteasome system independently of ubiquitination. The ligand IU1-248 is responsible for this direct binding to the proteasome. This ligand has been synthesized for its further use in the preparation of novel PROTACs in order to study their degradative capability.
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