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Development of a G4 Ligand-Conjugated Oligonucleotide Modality that Selectively Targets Individual G4 DNA Structures
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0001-6347-2169
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-202117OAI: oai:DiVA.org:umu-202117DiVA, id: diva2:1723088
Available from: 2023-01-02 Created: 2023-01-02 Last updated: 2023-01-02
In thesis
1. Redefining the essential molecular aspects that drive interactions between small molecules and G-quadruplex DNA
Open this publication in new window or tab >>Redefining the essential molecular aspects that drive interactions between small molecules and G-quadruplex DNA
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Omvärdering av de centrala molekylära aspekterna som styr interaktionen mellan små molekyler och G-quadruplex DNA
Abstract [en]

G-Quadruplex (G4) structures are secondary nucleic acid structures located in guanine-rich regions of DNA and RNA sequences, involved in gene regulation and cellular maintenance. Efforts to target G4s in a therapeutic setting are scarce, mainly due to vague details about the binding interactions between the ligands and the G4 structure combined with the lack of emphasis on drug-like properties early in the ligand development process. Furthermore, the ability to target specific G4 structures with small drug-like molecules remains a big challenge to overcome in the field. In this thesis, extensive organic synthesis developments coupled with computational-aided design and orthogonal in vitro assays has been used in tandem to reveal in-depth knowledge about ligand-to-G4 interactions. First, a macrocyclic approach was applied to design and discover novel G4 ligands which showed that macrocycles offer a solid foundation for ligand design. Next, computational tools to optimise the macrocyclic molecular conformation were used based on the macrocycles' abilities to stack on the G4 surface. In addition, macrocyclic, and non-macrocyclic ligands that bound G4 with high potency were shown to correlate with electron-deficient electrostatic potential (ESP) maps. The frequent inclusion of cationic residues in G4 ligands and their enhancement on ligand-to-G4 binding was, thereof, ascribed to their impact on the electrostatic character of the ligands' arene-arene interactions with the G4 surface, and not through direct electrostatic ionic interactions. In addition, the dispersion energetic component in the arene-arene interactions between the G4 ligand and the G4 was discovered to be paramount for ligand-to-G4 binding. The implementation of these descriptors in practice resulted in the discovery of potent G4 binders with adequate pharmacokinetic (PK) properties, accentuating the significance of understanding the molecular interactions between ligands and G4s in rational ligand design. Finally, a G4 ligand conjugated to an oligonucleotide was demonstrated as a modular approach to achieve selective binding of a ligand to a specific G4 structure. 

Place, publisher, year, edition, pages
Umeå: Umeå University, 2023. p. 73
Keywords
G-Quadruplexes, DNA, Oncogenes, G4 ligands, heterocycles, macrocycles, organic synthesis, molecular interactions, rational compound design, medicinal chemistry.
National Category
Organic Chemistry
Research subject
medicinal chemistry; Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-202119 (URN)978-91-7855-970-1 (ISBN)978-91-7855-969-5 (ISBN)
Public defence
2023-01-27, KB.E3.03 (stora hörsalen), KBC-huset, Universitetsområdet, 907 36 Umeå, Umeå, 09:00 (English)
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Available from: 2023-01-05 Created: 2023-01-02 Last updated: 2023-01-02Bibliographically approved

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Das, Rabindra NathBerner, AndreasBhuma, NareshAndréasson, MånsDoimo, MaraWanrooij, SjoerdChorell, Erik

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Das, Rabindra NathBerner, AndreasBhuma, NareshAndréasson, MånsDoimo, MaraWanrooij, SjoerdChorell, Erik
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Department of ChemistryDepartment of Medical Biochemistry and Biophysics
Biochemistry and Molecular BiologyOrganic Chemistry

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