Leiden Early Drug Discovery & Development

Lipid signaling in brain diseases

Multiple Sclerosis, Parkinson’s and Alzheimer’s disease are the most common neurodegenerative disorders. Unfortunately, no effective treatments are currently available to halt the progression of these neuroinflammatory diseases [1].

In recent years, based on transcriptomic analyses of post-mortem human tissue and work in mouse models, lipid signaling in microglial cells has gained scientific attention for the development of novel therapies for these neuroinflammatory diseases. Therefore, we are currently assessing lipase activity in human brain and preclinical models in collaboration with the Netherlands Institute for Neurosciences (NIN).

We have several hit- and lead optimization projects to modulate lipid signaling, including mono- and diacylglycerol lipase inhibitors, cannabinoid CB2 receptor agonists and NAPE-PLD inhibitors. [2-6] We have performed high throughput screens in collaboration with the European Lead Factory [2] and make use of chemical proteomics & structure-based design to guide the synthesis of new compounds, activity-based and fluorescent probes [3,5,6]. Hopefully, this will one day improve the lives of patients with these debilitating disorders.

References

1. Chiurchiù V, van der Stelt M, Centonze D, Maccarrone M. The endocannabinoid system and its therapeutic exploitation in multiple sclerosis: Clues for other neuroinflammatory diseases. Prog Neurobiol. 2018 Jan;160:82-100. doi: 10.1016/j.pneurobio.2017.10.007.
2. Mock ED, Mustafa M, Gunduz-Cinar O, Cinar R, Petrie GN, Kantae V, Di X, Ogasawara D, Varga ZV, Paloczi J, Miliano C, Donvito G, van Esbroeck ACM, van der Gracht AMF, Kotsogianni I, Park JK, Martella A, van der Wel T, Soethoudt M, Jiang M, Wendel TJ, Janssen APA, Bakker AT, Donovan CM, Castillo LI, Florea BI, Wat J, van den Hurk H, Wittwer M, Grether U, Holmes A, van Boeckel CAA, Hankemeier T, Cravatt BF, Buczynski MW, Hill MN, Pacher P, Lichtman AH, van der Stelt M. Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice. Nat Chem Biol. 2020 Jun;16(6):667-675. doi: 10.1038/s41589-020-0528-7.
3. Soethoudt M, Stolze SC, Westphal MV, van Stralen L, Martella A, van Rooden EJ, Guba W, Varga ZV, Deng H, van Kasteren SI, Grether U, IJzerman AP, Pacher P, Carreira EM, Overkleeft HS, Ioan-Facsinay A, Heitman LH, van der Stelt M. Selective Photoaffinity Probe That Enables Assessment of Cannabinoid CB2Receptor Expression and Ligand Engagement in Human Cells. J Am Chem Soc. 2018 May 16;140(19):6067-6075. doi: 10.1021/jacs.7b11281
4. Soethoudt M, Grether U, Fingerle J, Grim TW, Fezza F, de Petrocellis L, Ullmer C, Rothenhäusler B, Perret C, van Gils N, Finlay D, MacDonald C, Chicca A, Gens MD, Stuart J, de Vries H, Mastrangelo N, Xia L, Alachouzos G, Baggelaar MP, Martella A, Mock ED, Deng H, Heitman LH, Connor M, Di Marzo V, Gertsch J, Lichtman AH, Maccarrone M, Pacher P, Glass M, van der Stelt M. Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity. Nat Commun. 2017 Jan 3;8:13958. doi: 10.1038/ncomms13958.
5. Ogasawara D, Deng H, Viader A, Baggelaar MP, Breman A, den Dulk H, van den Nieuwendijk AM, Soethoudt M, van der Wel T, Zhou J, Overkleeft HS, Sanchez-Alavez M, Mori S, Nguyen W, Conti B, Liu X, Chen Y, Liu QS, Cravatt BF, van der Stelt M. Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition. Proc Natl Acad Sci U S A. 2016 Jan 5;113(1):26-33. doi: 10.1073/pnas.1522364112.
6. Baggelaar MP, Chameau PJ, Kantae V, Hummel J, Hsu KL, Janssen F, van der Wel T, Soethoudt M, Deng H, den Dulk H, Allarà M, Florea BI, Di Marzo V, Wadman WJ, Kruse CG, Overkleeft HS, Hankemeier T, Werkman TR, Cravatt BF, van der Stelt M. Highly Selective, Reversible Inhibitor Identified by Comparative Chemoproteomics Modulates Diacylglycerol Lipase Activity in Neurons. J Am Chem Soc. 2015 Jul 15;137(27):8851-7. doi: 10.1021/jacs.5b04883.