Biochemical and computational studies towards selective inhibition of the immunoproteasome
Masters thesis
Allardyce, D. 2018. Biochemical and computational studies towards selective inhibition of the immunoproteasome. Masters thesis Middlesex University Natural Sciences
Type | Masters thesis |
---|---|
Title | Biochemical and computational studies towards selective inhibition of the immunoproteasome |
Authors | Allardyce, D. |
Abstract | The proteasome pathway degrades >90% of cytosolic proteins deemed redundant, misfolded or toxic, thereby influencing key regulatory pathways including: cell cycle control, DNA repair and apoptosis. As such, proteasome inhibitors (PI) have exhibited broad therapeutic applications, particularly for multiple myeloma and mantle cell lymphoma with 3 inhibitors gaining FDA approval. However, covalent binding and lack of targeted action cause severe toxicity. Upon stimulation by inflammatory cytokines, constitutive proteasome (CP) active sites β1c, β2c and β5c are replaced with corresponding β1i, β2i and β5i subunits; forming the immunoproteasome (IP). The abundant CP is required for regular cell function, however due to upregulation in diseased states selective IP inhibition is associated with an increased therapeutic index. Recent identification of structural differences between CP and IP specificity pockets (S1-4) allows structure-based drug design. |
Department name | Natural Sciences |
Institution name | Middlesex University |
Publication dates | |
12 Feb 2018 | |
Publication process dates | |
Deposited | 12 Feb 2018 |
Accepted | 07 Feb 2018 |
Output status | Published |
Accepted author manuscript | |
Language | English |
https://repository.mdx.ac.uk/item/87725
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