A toolbox of promiscuous immobilisation chemistries to identify the targets of natural compounds by chemoproteomics (PromisChemProt)
Biological and Biomimetic Chemistry
Final Report Abstract
Many naturally occurring substances form the basis for active medical ingredients. Wellknown examples are taxol from the yew tree, which is used to treat cancer, or so-called digitalglycosides from the red foxglove, which are used to treat heart failure. Almost all of these drugs act on proteins in the human body in order to exert their effect. However, it is often not known exactly which proteins are involved. This makes it difficult to develop drugs based on natural substances. The aim of this research project was therefore to develop methods and processes that would make this more successful than before. In order to achieve this objective, the researchers used chemical and photo-chemical methods to first attach the natural substances to be analysed to a solid phase - or more precisely to small beads - in order to then literally fish out the target proteins from protein extracts of human cancer cells. This method is also known as affinity chromatography. The proteins isolated in this way were subsequently identified using mass spectrometry and bioinformatic methods. To this end, the researchers tried out a number of different chemical reactions (with and without the aid of strong UV light) that were intended to modify the natural products as random as possible. This approach was chosen primarily because the targeted chemical synthesis of such chemcial ‘fishing rods’ is not only very time-consuming, but also often prevents the specific interaction of the natural product with its target protein. The approaches using strong UV light have proved to be particularly successful. A good 80% of the natural substances analysed could be transformed into affinity probes in this way and in 36% of cases the target protein was found. This success rate exceeded the expectations of the researchers as natural products have an almost infinite variety of chemical structures and it was therefore not necessarily to be expected that a single method would often work. The relevance of these results may be judged by the fact that currently about 35% of all drugs are either natural products or their development was inspired by the effects of natural products. This project has thus provided a valuable methodological contribution to research on natural products as the basis for drugs and it is to be expected that the method will be widely used in the early phases of drug development.
Publications
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Merits of Diazirine Photo-Immobilization for Target Profiling of Natural Products and Cofactors. ACS Chemical Biology, 17(11), 3100-3109.
Prokofeva, Polina; Höfer, Stefanie; Hornisch, Maximilian; Abele, Miriam; Kuster, Bernhard & Médard, Guillaume
