• Deutsch
    • English
  • English 
    • Deutsch
    • English
  • Login
Item View 
  •   Home
  • Naturwissenschaften, Mathematik und Informatik
  • Fakultät für Chemie (inkl. GAUSS)
  • Item View
  •   Home
  • Naturwissenschaften, Mathematik und Informatik
  • Fakultät für Chemie (inkl. GAUSS)
  • Item View
JavaScript is disabled for your browser. Some features of this site may not work without it.

Design and synthesis of multifunctional ligands to study and prevent aggregation processes in Amyotrophic Lateral Sclerosis proteins

by Viktoria Mrđen Debono
Doctoral thesis
Date of Examination:2020-12-11
Date of issue:2021-02-22
Advisor:Prof. Dr. Ulf Diederichsen
Referee:Prof. Dr. Ulf Diederichsen
Referee:Prof. Dr Franziska Jun.-Thomas
Referee:Prof. Dr. Kai Tittmann
Referee:Prof. Dr. Lutz Ackermann
Referee:Dr. Luis Felipe Opazo Dávila
Referee:Dr. Holm Frauendorf
crossref-logoPersistent Address: http://dx.doi.org/10.53846/goediss-8443

 

 

Files in this item

Name:Thesis_Mrđen Debono Viktoria_20210213_digital.pdf
Size:15.7Mb
Format:PDF
Description:Dissertation
ViewOpen

The following license files are associated with this item:


Abstract

English

Amyotrophic lateral sclerosis (ALS) is an incurable lethal disease that affects motor neurons and its heterogeneity is reflected in various mutations among the sporadic ALS (sALS) and familial ALS (fALS) disease types. Superoxide dismutase-1 (SOD1), as a cell guardian, is an essential protein needed for the antioxidative cellular homeostasis but is many times a silent traitor in both types of ALS. The exact mechanisms by which SOD1 mutations contribute to ALS are still not fully understood, but structural investigations have interestingly revealed that the protein is a homodimer. It is suggested that the most severe mutations disrupt the dimer interface, causing dissociation, misfolding, and protein aggregation, which are the main sources of toxicity. Additionally, the aggregation processes trigger many other mechanisms, and correlation between the mutants’ structural damage and aggregation pathways remains a puzzle. In this thesis, in silico docking studies are done to design multifunctional ligands, whose biphenyl core structures mitigate the aggregation of a severe dimer interface mutant. A modular synthetic approach is developed, and different ligands are synthesized to anchor the protein dimer while preventing protein dissociation. Protein-ligand interactions, affinity, and their behaviour are then investigated via microscale thermophoresis, isothermal calorimetry, and aggregation assays. It is shown that synthesized ligands with aromatic substituents have a higher binding affinity toward the protein, and that they could reduce the aggregation of the SOD1 mutant. Additionally, the principle that the ligands can mediate a transfer of a fluorescent dye onto a target amino acid shows their multifunctionality. The design of affinity-based fluorogenic probes is envisaged as an extended approach and should assist to understand the mechanisms leading to SOD1-related ALS.
Keywords: Amyotrophic lateral sclerosis; Superoxide dismutase-1; ALS; SOD1; protein aggregation; aggregation assays; synthesis
 

Statistik

Publish here

Browse

All of eDissFaculties & ProgramsIssue DateAuthorAdvisor & RefereeAdvisorRefereeTitlesTypeThis FacultyIssue DateAuthorAdvisor & RefereeAdvisorRefereeTitlesType

Help & Info

Publishing on eDissPDF GuideTerms of ContractFAQ

Contact Us | Impressum | Cookie Consents | Data Protection Information
eDiss Office - SUB Göttingen (Central Library)
Platz der Göttinger Sieben 1
Mo - Fr 10:00 – 12:00 h


Tel.: +49 (0)551 39-27809 (general inquiries)
Tel.: +49 (0)551 39-28655 (open access/parallel publications)
ediss_AT_sub.uni-goettingen.de
[Please replace "_AT_" with the "@" sign when using our email adresses.]
Göttingen State and University Library | Göttingen University
Medicine Library (Doctoral candidates of medicine only)
Robert-Koch-Str. 40
Mon – Fri 8:00 – 24:00 h
Sat - Sun 8:00 – 22:00 h
Holidays 10:00 – 20:00 h
Tel.: +49 551 39-8395 (general inquiries)
Tel.: +49 (0)551 39-28655 (open access/parallel publications)
bbmed_AT_sub.uni-goettingen.de
[Please replace "_AT_" with the "@" sign when using our email adresses.]