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Natural products applied in reverse chemical proteomics

thesis
posted on 28.03.2022, 09:24 by Michael Gotsbacher
Natural products are a rich source of structurally diverse and biologically active small molecules. They constitute a useful class of compounds as leads in rational drug design and development. However, drug discovery faces a major bottleneck due to the lack of knowledge about the active compounds' cellular targets and mode of action. For this thesis, several natural products with interesting biological activity have been applied as ligands in a technique we refer to as reverse chemical proteomics. This method rapidly generates protein-ligand pairs, which will be useful for the rational design of new and more potent therapeutics, identification of druggable targets as well as for understanding the underlying biochemical pathways of these active ligands. This thesis is divided into four main chapters. Chapter 1 introduces the techniques behind reverse chemical proteomics. Chapter 2 describes the bioassay-guided fractionation of eleven marine sponges, the isolation and characterisation of two new and seven known bromotyrosines of the highly antibacterial active extract from the marine sponge Pseudoceratina purpurea, as well as isolation of bromotyrosines from the opisthobranch Tylodina corticalis, which was collected while feeding on P. purpurea. In Chapter 3, the chemical derivatisation of natural products is presented alongside the synthesis and characterisation of novel, linkers and reagents required for performing reverse chemical proteomics. Chapter 4 describes the application of T7 phage display utilising the immunosuppressant natural product FK506 as a model affinity probe. Consecutively, protein binding partners for biotinylated artesunate, daptomycin and manzamine are isolated from various T7 phage-displayed human cDNA libraries. An experimental chapter and concluding remarks follow thereafter.

History

Table of Contents

1. Introduction -- 2. Marine natural products -- 3. Synthesis of linkers, reagents and biotinylated probes -- 4. Display cloning -- 5. Experimental -- 6. Conclusions and future directions.

Notes

"2012 A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy" Includes bibliographical references

Awarding Institution

Macquarie University

Degree Type

Thesis PhD

Degree

Thesis (PhD), Macquarie University, Faculty of Science, Department of Chemistry and Biomolecular Sciences

Department, Centre or School

Dept. of Chemistry and Biomolecular Sciences

Year of Award

2013

Principal Supervisor

Peter Karuso

Rights

Copyright disclaimer: http://www.copyright.mq.edu.au Copyright Michael Gotsbacher 2013.

Language

English

Extent

1 online resource (xx, 384 pages) illustrations (some colour)

Former Identifiers

mq:27168 http://hdl.handle.net/1959.14/229748 1970474