ETD

Digital archive of theses discussed at the University of Pisa

 

Thesis etd-10092020-151429


Thesis type
Tesi di laurea magistrale LM5
Author
BELLI, GIORGIA
URN
etd-10092020-151429
Thesis title
NLPR3 inflammasome and its role in inflammatory disease: design and synthesis of indolone derivatives.
Department
FARMACIA
Course of study
CHIMICA E TECNOLOGIA FARMACEUTICHE
Supervisors
relatore Prof.ssa La Motta, Concettina
correlatore Dott. Petrarolo, Giovanni
Keywords
  • inflammasome
  • inhibitors
  • NLRP3
Graduation session start date
04/11/2020
Availability
Withheld
Release date
04/11/2090
Summary
The NLRP3 inflammasome is a multiprotein complex that is physiologically activated in response to the endogenous and exogenous stimulation of the innate immune system cells, which aims to ensure a normal inflammatory response leading to the production of pro-inflammatory mediators and cytokines, including the more characteristic IL-1β and IL-18. These latter are responsible for the initiation of the inflammatory cascade and, by recalling other immunity cells, have the purpose of resolving the infection. However, a deregulation of this process leads to an excessive inflammatory reaction which is at the basis of numerous autoinflammatory diseases (CAPS), neurodegenerative (Alzheimer’s, Parkinson’s and multiple sclerosis), but also metabolic disorders (type II diabetes, gout and obesity). For this reason, research has focused on the development of new synthetic molecules designed with the aim of inhibiting the formation of this complex and thus reducing excessive inflammation. In this paper, the main natural and synthetic inhibitors known to date will be discussed, with particular attention to those aimed at the ATP-ase site of the central protein of the complex, the NLRP3 protein. Moreover, given the current importance of emerging COVID-19 epidemic, the potential involvement of NLRP3 in the onset and development of the most severe symptoms associated with cytokine storm and acute respiratory distress syndrome (ARDS) will be evaluated.
The objective of this thesis is the synthesis of compounds characterized by the presence of a 2-oxindole nucleus, suitably substituted in position 5 of the benzene moiety, potentially able to interact with the NLRP3 ATP-ase site, inactivating it and blocking the excessive production of inflammatory mediators.
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