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Start of funding 01.01.2019

Discovery and development of natural product-based neuroprotective compounds and elucidation of their molecular mode of action

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Natural products hold considerable interest for the development of novel neuroprotectants, and therefore hold potential as disease-modifying compounds for treatment neurodegenerative disorders like Alzheimer’s disease. Using the phenotypic screening approach, we aim to investigate novel chemical derivatives of natural product as well as hybrids of natural products to reveal and investigate the pharmacophores responsible for their biological activities. Key part of the project is the elucidation of intracellular targets of these compounds, as they show pronounced neuroprotective effects, but their molecular mode of actions remain unsolved. For this purpose, special chemical derivatives will be developed and applied. Subsequently, we aim to optimize the compounds’ features to make them more suitable to potential therapeutic applications.

Final report:
Activities

Within the BaCaTeC-funded project “Discovery and development of natural product-based neuroprotective compounds and elucidation of their molecular mode of action” two stays for two monts each of a Würzburg PhD student and a one-week stay of the Bavarian principal investigator were funded between the Pharmaceutical and Medicinal Chemistry Laboratory (Prof. Dr. Michael Decker) at the Institute of Pharmacy and Food Chemistry and the Cellular Neurobiology Laboratory (Dr. Pamela Maher) of the Salk Institute for Biological Studies at La Jolla, California.>
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Output

Within the funded project three scientific and peer-reviewed publications were published describing the research conducted and goals achieved:
1) „Studies into the flavonoid sterubin: total synthesis, enantioseparation, enantiopurity in nature, neuroprotectivity in vitro and in vivo” J. Hofmann, S. Saef, M. Scheiner, M. Hoffmann, S. Oertler, A. Appelt-Menzel, P. Maher, T. Maurice, G. Bringmann*, M. Decker* Chem. Eur. J. 2020, 26, 7299–7308 – IF = 4.9
2) „7-O-Esters of taxifolin with pronounced overadditive effects in neuroprotection, anti-neuroinflammation and short-term memory” - IF = 10.0 S. Gunesch, M. Hoffmann, C. Kiermeier, W. Fischer, A. Pinto, T. Maurice, P. Maher*, M. Decker* Redox Biol. 2020, 29, 101378
3) “Development and application of a chemical probe based on a neuroprotective flavonoid hybrid for target identification using activity-based protein profiling” - IF = 4.5 S. Gunesch, D. Soriano-Castell, S. Lamer, A. Schlosser, P. Maher*, M. Decker*, ACS Chem. Neurosci. 2020, 11(22), 3823-3837
BaCaTeC-funded scientists bold.

1) The first publication describes the total synthesis of the natural product and flavanone sterubin, which had been intensively characterized and described as a neuroprotectant in the Cellular Neurobiology Lab at Salk. Previously, the compound had to be isolated and purified from a plant and is now available in large quantities and providing easy access for chemical modifications. In this publication we could describe and identify for the first time the natural occurrence of the enantiopure form in the plant and also described the activity of this flavanone in an Alzheimer disease mouse model.

2) The second publication deals with one of the core questions to be investigated within the collaboration, i.e. the improvement of neuroprotective properties of the starting natural products and their application as drug discovery candidates for Alzheimer’s disease. For this reason, hybrid molecules of the flavonoid taxifolin and phenolic acids, namely cinnamic and ferulic acids, were synthesized at Würzburg and investigated in vitro in biological assays. These studies were complemented in advanced assays regarding aging and Alzheimer’s at Salk, which showed pronounced overadditive effects over the starting natural products (exytosis, ferroptosis, ATP depletion in a murine hippocampal neuronal cell line as well as reduction of LPS-induced neuroinflammation in microglia cells as assessed by effects on the levels of nitric oxide, interleukine 6 and tumor necrosis factor alpha).
Encouraged by these results, one compound was evaluated in the laboratory of a collaboration partner at INSERM and University of Montpellier in an in vivo Alzheimer’s disease mouse model and exhibited improvement of short-term memory at a dosage of 3 mg/kg, again in an over-additive manner. These results are not only promising regarding drug discovery, but they prove that such natural product hybrids indeed show in vivo activity and pass the blood-brain-barrier. Such pronounced effects can hardly been explained by unspecific “antioxidant” effects and therefore in this work first hints for specific intracellular pathways stabilizing glutathione levels in the cell were found, such as influence on Nrf2 signaling.

3) Building on the promising results of the above publication, the research groups developed molecular probes based on the most active hybrid molecules for “target-fishing”, i.e. target identification using activity-based protein profiling (also termed “chemical genomics”).
Based on our previous structure-activity relationships, a respective molecular probe was developed that showed comparable influence on the same intracellular pathways as the lead compound. This probe was applied in fluorescence microscopy after chemical coupling to a dye and it visualized enrichment in mitochondria, a cell structure with particular relevance in aging and neurodegenerative diseases. Target identification experiments using affinity pulldown and mass spectroscopic analysis (the latter performed at the Rudolf-Virchow-Center at Würzburg) identified several intracellular interaction partners, which in turn were validated in siRNA knockdown experiments at Salk Institute.
This work explains the high activity of the hybrids and identifies putative specific targets of such natural products, such as sarco/endoplasmatic reticulum calcium ATPase (SERCA). Outlook

Through the initial funding of the BaCaTec several scientific projects could be successfully conducted and already at this stage additional third-party funding could be secured by the German Academic Exchange Service (2020-21). Naturally, novel questions arise from the results obtained, that might be investigated by the support of subsequent BaCaTeC funding and/or other third-party funding. It remains to be answered how it is possible to obtain chemically and metabolically stable natural products hybrids with the same or even improved biological/pharmacological activities. The chemical genomics approach can be also applied to other natural products, such as compounds described by the Californian partner laboratory to obtain molecular probes in order to identify its molecular target structure in the living cell.