ETD system

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Tesi etd-10192017-213313

Thesis type
Tesi di laurea magistrale LM5
Deconstruction of small-molecule Keap1 inhibitors
Corso di studi
relatore Prof.ssa La Motta, Concettina
relatore Prof. Bach, Anders
Parole chiave
  • Oxidative stress
  • Multitarget drug
  • Keap1
  • Ischaemic stroke
  • CNS permeability
  • Fragment based drug design
Data inizio appello
Secretata d'ufficio
Data di rilascio
Riassunto analitico
Ischaemic stroke is caused by blood cot that blocks blood supply to the brain and it is the second leading cause of death and the leading cause of disability worldwide. Depletion of oxygen and glucose, due to blood flow reduction, initiates a series of biochemical reactions after minutes of ischaemia, together called ischaemic cascade, that lead to neurological damage. At present, the only therapy available is focuses on restoring an adequate flow of blood to the brain by breaking the clot down or by removing it mechanically. Although both treatments show benefits for several patients, their substantial limitations, such as need for intervention within the first few hours, risk of bleeding and reperfusion injury, significantly restrict the treatment efficacy.
The production of reactive oxygen species (ROS), resulting in oxidative stress, plays a central role in the ischaemic cascade. The transcription of many antioxidants enzymes is regulated by the transcription factor Nfr2. An emerging therapeutic strategy against ischaemic stroke is to disrupt the protein-protein interaction (PPI) between Nrf2 and its repressor protein Keap1, thus boosting the Nrf2-dependent defence against ROS. Several small-molecule inhibitors able to disrupt the Keap1-Nrf2 interaction have been reported to date, but they all have low CNS permeability.
Fragment-based drug design (FBDD) is a key issue in this project. Specifically, some known inhibitors have been deconstructed and the designed fragments have been synthe- sised to generate a relative small library of fragments structurally predisposed to bind the target. Active fragments may define the direction for further structural elaboration and optimization and at a later stage these selected fragments may be reconstructed into a new scaffold trying to achieve an active compound able to reach the CNS. Most of obtained fragments library have been tested in fluorescent polarization and thermofluor assays. Preliminary results show binding to Keap1 for some fragments, likely demonstrating the potential use of the deconstruction approach in the discovery of novel fragment-binders to Keap1.