Publicação
Targeting the ubiquitin-proteasome system: four-membered ring inhibitors of proteasome
| Resumo: | The ubiquitin-proteasome system (UPS) plays a pivotal role in the degradation of proteins in cellular homeostasis, with the 20S proteasome (core particle, CP) being the proteolytic key component of the UPS. The catalytic active sites of the cylinder-shaped, multimeric, CP are formed by N-terminal threonines, which are located at subunits β1, β2, and β5 in the inner cavity of a barrel-like structure. Several natural β-lactones such as Omuralide and Marizomib, were found to predominantly bind to subunit β5 that harbors the chymotrypsin-like (CTL) activity. Although at least one β-lactone is now in clinical use, this scaffold is very reactive and thus prone to metabolic inactivation and off-target effects. Our group has developed β-lactam-based systems as inhibitors of serine proteases from the chymotrypsin super-family. These inhibitors can be appropriately modified to modulate not only the molecular recognition by the enzyme, but also the intrinsic reactivity towards the catalytic amino acid. In this project we tried to design and synthesize a small library of 4-oxo-β-lactams compounds as proteasome inhibitors, containing the structural motifs for molecular recognition by proteasome, and we evaluated the inhibitory activity against the proteasomes, using a fluorometric proteasome 20S assay. This is a homogeneous fluorescent assay that measures the CTL protease activity solution or in cultured cells. Unfortunately, the compounds synthesized in this project did not show a considerable inhibitory effect on proteasome. The best compound in this series was compound 39. |
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| Autores principais: | Heydarpour Klidsar, Maryam |
| Assunto: | Ubiquitin-proteasome system ß-lactam scaffold Proteasome inhibitor Chymotrypsin-like (CTL) activity Teses de mestrado - 2019 |
| Ano: | 2019 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | The ubiquitin-proteasome system (UPS) plays a pivotal role in the degradation of proteins in cellular homeostasis, with the 20S proteasome (core particle, CP) being the proteolytic key component of the UPS. The catalytic active sites of the cylinder-shaped, multimeric, CP are formed by N-terminal threonines, which are located at subunits β1, β2, and β5 in the inner cavity of a barrel-like structure. Several natural β-lactones such as Omuralide and Marizomib, were found to predominantly bind to subunit β5 that harbors the chymotrypsin-like (CTL) activity. Although at least one β-lactone is now in clinical use, this scaffold is very reactive and thus prone to metabolic inactivation and off-target effects. Our group has developed β-lactam-based systems as inhibitors of serine proteases from the chymotrypsin super-family. These inhibitors can be appropriately modified to modulate not only the molecular recognition by the enzyme, but also the intrinsic reactivity towards the catalytic amino acid. In this project we tried to design and synthesize a small library of 4-oxo-β-lactams compounds as proteasome inhibitors, containing the structural motifs for molecular recognition by proteasome, and we evaluated the inhibitory activity against the proteasomes, using a fluorometric proteasome 20S assay. This is a homogeneous fluorescent assay that measures the CTL protease activity solution or in cultured cells. Unfortunately, the compounds synthesized in this project did not show a considerable inhibitory effect on proteasome. The best compound in this series was compound 39. |
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