Design and synthesis of novel bisubstrate analogues of ppGpp containing diphosphate isosteres as potential RSH enzyme inhibitors

Abstract: The status quo of modern antibiotics comprises of an ever growing emergence of resistance against them and an ever shrinking discovery of new classes of antibiotic drugs. Researchers have long tried to find alternative ways to combat antibiotic resistance. Stringent response is a bacterial survival mechanism that is characterized by the overproduction of two nucleotides, collectively referred to as (p)ppGpp, under stress conditions. This mechanism has been associated with the ability of bacteria to develop resistance and its inhibition has been a target for the design of novel antibiotics.
In this thesis, novel (p)ppGpp analogues are designed using dipeptides as diphosphate mimics. Based on the mechanism of the enzyme synthesizing (p)ppGpp, the molecules consist of guanosine and adenosine derivatives connected together via an amino acid “bridge”. Through docking experiments the best amino acid combinations, as well as the length of the chain are determined. Guanosine and adenosine derivatives as the main building blocks are synthesized. Amino acids or dipeptides are coupled to the nucleoside compounds via solution and solid phase peptide synthesis. A final bisubstrate analogue is synthesized.
In the second project of this thesis, the concept of diphosphate mimics is employed as well in the design of Complex I inhibitors. As part of the mitochondrial electron transport chain, Complex I is crucial for eukaryotic cells and researchers are keen to find more potent inhibitors in order to shed light on the enzyme’s intricate mechanism. Docking experiments revealed a promising inhibitor. Optimized derivatives are synthesized and tested in vitro and / or co-crystalized with enzyme. A triol derivative is found to have great alignment and interactions inside the active pocket. Efforts to continue to grow the molecule by incorporating a terminal amino group are made.
In vitro testing of the (p)ppGpp analogues in the future will allow the optimization of the amino acid bridge and continuation of growing the molecule in order to enhance its inhibitory activity. Finally, addition of a squaramide moiety to the triol derivative will enable the selective coupling with various functionalized groups and a screening of potential Complex I inhibitors will be possible

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Universität Freiburg, Dissertation, 2023

Classification and Topics

• Keyword: Chemische Synthese ; Inhibitor ; Stringente Kontrolle ; Guanosinderivate ; Adenosinderivate ; Docking

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2023
• Creator: Fouka, Paraskevi
• Contributor: Jessen, Henning Jacob ; Günther, Stefan ; Albert-Ludwigs-Universität Freiburg. Fakultät für Chemie und Pharmazie ; Albert-Ludwigs-Universität Freiburg. Institut für Organische Chemie

Further information

• DOI: 10.6094/UNIFR/237258
• URN: urn:nbn:de:bsz:25-freidok-2372582
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 14.08.2025, 10:59 AM CEST