Honors & Awards

  • ETH Medal for Outstanding Dissertations, ETH Zürich (May 2022)
  • SNF Postdoc.Mobility Fellowship, Swiss National Science Foundation (February 2022)
  • El Sohly Award for Excellence in Cannabis Chemistry, American Chemical Society (March 2022)

Program Affiliations

Stanford Advisors

All Publications

  • Flipping the GPCR Switch: Structure-Based Development of Selective Cannabinoid Receptor 2 Inverse Agonists ACS CENTRAL SCIENCE Kosar, M., Sarott, R. C., Sykes, D. A., Viray, A. G., Vitale, R., Tomasevic, N., Li, X., Ganzoni, R. Z., Kicin, B., Reichert, L., Patej, K. J., Gomez-Bouzo, U., Guba, W., McCormick, P. J., Hua, T., Gruber, C. W., Veprintsev, D. B., Frank, J. A., Grether, U., Carreira, E. M. 2024
  • Chemical Specification of E3 Ubiquitin Ligase Engagement by Cysteine-Reactive Chemistry. Journal of the American Chemical Society Sarott, R. C., You, I., Li, Y. D., Toenjes, S. T., Donovan, K. A., Seo, P., Ordonez, M., Byun, W. S., Hassan, M. M., Wachter, F., Chouchani, E. T., Słabicki, M., Fischer, E. S., Ebert, B. L., Hinshaw, S. M., Gray, N. S. 2023


    Targeted protein degradation relies on small molecules that induce new protein-protein interactions between targets and the cellular protein degradation machinery. Most of these small molecules feature specific ligands for ubiquitin ligases. Recently, the attachment of cysteine-reactive chemical groups to pre-existing small molecule inhibitors has been shown to drive specific target degradation. We demonstrate here that different cysteine-reactive groups can specify target degradation via distinct ubiquitin ligases. By focusing on the bromodomain ligand JQ1, we identify cysteine-reactive functional groups that drive BRD4 degradation by either DCAF16 or DCAF11. Unlike proteolysis-targeting chimeric molecules (PROTACs), the new compounds use a single small molecule ligand with a well-positioned cysteine-reactive group to induce protein degradation. The finding that nearly identical compounds can engage multiple ubiquitination pathways suggests that targeting cellular pathways that search for and eliminate chemically reactive proteins is a feasible avenue for converting existing small molecule drugs into protein degrader molecules.

    View details for DOI 10.1021/jacs.3c06622

    View details for PubMedID 37767920

  • Cobalt-Catalyzed Aerobic Aminocyclization of Unsaturated Amides for the Synthesis of Functionalized ?- and d-Lactams ORGANIC LETTERS Freis, M., Balkenhohl, M., Fischer, D. M., Georgiev, T., Sarott, R. C., Carreira, E. M. 2023; 25 (34): 6380-6384


    We report the cobalt-catalyzed aminocyclization of unsaturated N-acyl sulfonamides in the presence of oxygen to provide γ- and δ-lactam aldehydes. Use of an optically active cobalt catalyst resulted in the formation of enantiomerically enriched γ-and δ-lactam alcohols. The γ-lactam aldehydes and alcohols obtained were elaborated into useful building blocks.

    View details for DOI 10.1021/acs.orglett.3c02390

    View details for Web of Science ID 001060920200001

    View details for PubMedID 37610083

    View details for PubMedCentralID PMC10476186

  • Platform Reagents Enable Synthesis of Ligand-Directed Covalent Probes: Study of Cannabinoid Receptor 2 in Live Cells. Journal of the American Chemical Society Kosar, M., Sykes, D. A., Viray, A. E., Vitale, R. M., Sarott, R. C., Ganzoni, R. L., Onion, D., Tobias, J. M., Leippe, P., Ullmer, C., Zirwes, E. A., Guba, W., Grether, U., Frank, J. A., Veprintsev, D. B., Carreira, E. M. 2023; 145 (28): 15094-15108


    Pharmacological modulation of cannabinoid receptor type 2 (CB2R) holds promise for the treatment of neuroinflammatory disorders, such as Alzheimer's disease. Despite the importance of CB2R, its expression and downstream signaling are insufficiently understood in disease- and tissue-specific contexts. Herein, we report the first ligand-directed covalent (LDC) labeling of CB2R enabled by a novel synthetic strategy and application of platform reagents. The LDC modification allows visualization and study of CB2R while maintaining its ability to bind other ligands at the orthosteric site. We employed in silico docking and molecular dynamics simulations to guide probe design and assess the feasibility of LDC labeling of CB2R. We demonstrate selective, covalent labeling of a peripheral lysine residue of CB2R by exploiting fluorogenic O-nitrobenzoxadiazole (O-NBD)-functionalized probes in a TR-FRET assay. The rapid proof-of-concept validation with O-NBD probes inspired incorporation of advanced electrophiles suitable for experiments in live cells. To this end, novel synthetic strategies toward N-sulfonyl pyridone (N-SP) and N-acyl-N-alkyl sulfonamide (NASA) LDC probes were developed, which allowed covalent delivery of fluorophores suitable for cellular studies. The LDC probes were characterized by a radioligand binding assay and TR-FRET experiments. Additionally, the probes were applied to specifically visualize CB2R in conventional and imaging flow cytometry as well as in confocal fluorescence microscopy using overexpressing and endogenously expressing microglial live cells.

    View details for DOI 10.1021/jacs.2c13629

    View details for PubMedID 37401816

  • Cannabinoid CB2 Receptors Modulate Microglia Function and Amyloid Dynamics in a Mouse Model of Alzheimer's Disease FRONTIERS IN PHARMACOLOGY Ruiz de Martin Esteban, S., Benito-Cuesta, I., Terradillos, I., Martinez-Relimpio, A. M., Arnanz, M., Ruiz-Perez, G., Korn, C., Raposo, C., Sarott, R. C., Westphal, M. V., Elezgarai, I., Carreira, E. M., Hillard, C. J., Grether, U., Grandes, P., Grande, M., Romero, J. 2022; 13: 841766


    The distribution and roles of the cannabinoid CB2 receptor in the CNS are still a matter of debate. Recent data suggest that, in addition to its presence in microglial cells, the CB2 receptor may be also expressed at low levels, yet biologically relevant, in other cell types such as neurons. It is accepted that the expression of CB2 receptors in the CNS is low under physiological conditions and is significantly elevated in chronic neuroinflammatory states associated with neurodegenerative diseases such as Alzheimer's disease. By using a novel mouse model (CB2 EGFP/f/f), we studied the distribution of cannabinoid CB2 receptors in the 5xFAD mouse model of Alzheimer's disease (by generating 5xFAD/CB2 EGFP/f/f mice) and explored the roles of CB2 receptors in microglial function. We used a novel selective and brain penetrant CB2 receptor agonist (RO6866945) as well as mice lacking the CB2 receptor (5xFAD/CB2 -/-) for these studies. We found that CB2 receptors are expressed in dystrophic neurite-associated microglia and that their modulation modifies the number and activity of microglial cells as well as the metabolism of the insoluble form of the amyloid peptide. These results support microglial CB2 receptors as potential targets for the development of amyloid-modulating therapies.

    View details for DOI 10.3389/fphar.2022.841766

    View details for Web of Science ID 000801762700001

    View details for PubMedID 35645832

    View details for PubMedCentralID PMC9136843

  • Detection of cannabinoid receptor type 2 in native cells and zebrafish with a highly potent, cell-permeable fluorescent probe CHEMICAL SCIENCE Gazzi, T., Brennecke, B., Atz, K., Korn, C., Sykes, D., Forn-Cuni, G., Pfaff, P., Sarott, R. C., Westphal, M., Mostinski, Y., Mach, L., Wasinska-Kalwa, M., Weise, M., Hoare, B. L., Miljus, T., Mexi, M., Roth, N., Koers, E. J., Guba, W., Alker, A., Rufer, A. C., Kusznir, E. A., Huber, S., Raposo, C., Zirwes, E. A., Osterwald, A., Pavlovic, A., Moes, S., Beck, J., Nettekoven, M., Benito-Cuesta, I., Grande, T., Drawnel, F., Widmer, G., Holzer, D., van der Wel, T., Mandhair, H., Honer, M., Fingerle, J., Scheffel, J., Broichhagen, J., Gawrisch, K., Romero, J., Hillard, C. J., Varga, Z. V., van der Stelt, M., Pacher, P., Gertsch, J., Ullmer, C., McCormick, P. J., Oddi, S., Spaink, H. P., Maccarrone, M., Veprintsev, D. B., Carreira, E. M., Grether, U., Nazare, M. 2022; 13 (19): 5539-5545

    View details for DOI 10.1039/d1sc06659e

    View details for Web of Science ID 000784920900001

  • Light-mediated discovery of surfaceome nanoscale organization and intercellular receptor interaction networks NATURE COMMUNICATIONS Muller, M., Grabnitz, F., Barandun, N., Shen, Y., Wendt, F., Steiner, S. N., Severin, Y., Vetterli, S. U., Mondal, M., Prudent, J. R., Hofmann, R., van Oostrum, M., Sarott, R. C., Nesvizhskii, A. I., Carreira, E. M., Bode, J. W., Snijder, B., Robinson, J. A., Loessner, M. J., Oxenius, A., Wollscheid, B. 2021; 12 (1): 7036


    The molecular nanoscale organization of the surfaceome is a fundamental regulator of cellular signaling in health and disease. Technologies for mapping the spatial relationships of cell surface receptors and their extracellular signaling synapses would unlock theranostic opportunities to target protein communities and the possibility to engineer extracellular signaling. Here, we develop an optoproteomic technology termed LUX-MS that enables the targeted elucidation of acute protein interactions on and in between living cells using light-controlled singlet oxygen generators (SOG). By using SOG-coupled antibodies, small molecule drugs, biologics and intact viral particles, we demonstrate the ability of LUX-MS to decode ligand receptor interactions across organisms and to discover surfaceome receptor nanoscale organization with direct implications for drug action. Furthermore, by coupling SOG to antigens we achieved light-controlled molecular mapping of intercellular signaling within functional immune synapses between antigen-presenting cells and CD8+ T cells providing insights into T cell activation with spatiotemporal specificity. LUX-MS based decoding of surfaceome signaling architectures thereby provides a molecular framework for the rational development of theranostic strategies.

    View details for DOI 10.1038/s41467-021-27280-x

    View details for Web of Science ID 000727618000002

    View details for PubMedID 34857745

  • Optical Control of Cannabinoid Receptor 2-Mediated Ca2+ Release Enabled by Synthesis of Photoswitchable Probes JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Sarott, R. C., Viray, A. G., Pfaff, P., Sadybekov, A., Rajic, G., Katritch, V., Carreira, E. M., Frank, J. A. 2021; 143 (2): 736-743


    Cannabinoid receptor 2 (CB2) is a promising target for the treatment of neuroinflammation and other diseases. However, a lack of understanding of its complex signaling in cells and tissues complicates the therapeutic exploitation of CB2 as a drug target. We show for the first time that benchmark CB2 agonist HU308 increases cytosolic Ca2+ levels in AtT-20(CB2) cells via CB2 and phospholipase C. The synthesis of photoswitchable derivatives of HU308 from the common building block 3-OTf-HU308 enables optical control over this pathway with spatiotemporal precision, as demonstrated in a real-time Ca2+ fluorescence assay. Our findings reveal a novel messenger pathway by which HU308 and its derivatives affect cellular excitability, and they demonstrate the utility of chemical photoswitches to control and monitor CB2 signaling in real-time.

    View details for DOI 10.1021/jacs.0c08926

    View details for Web of Science ID 000612557200028

    View details for PubMedID 33399457

  • Development of High-Specificity Fluorescent Probes to Enable Cannabinoid Type 2 Receptor Studies in Living Cells JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Sarott, R. C., Westphal, M., Pfaff, P., Korn, C., Sykes, D. A., Gazzi, T., Brennecke, B., Atz, K., Weise, M., Mostinski, Y., Hompluem, P., Koers, E., Miljus, T., Roth, N. J., Asmelash, H., Vong, M. C., Piovesan, J., Guba, W., Rufer, A. C., Kusznir, E. A., Huber, S., Raposo, C., Zirwes, E. A., Osterwald, A., Pavlovic, A., Moes, S., Beck, J., Benito-Cuesta, I., Grande, T., de Martin Esteban, S., Yeliseev, A., Drawnel, F., Widmer, G., Holzer, D., van der Wel, T., Mandhair, H., Yuan, C., Drobyski, W. R., Saroz, Y., Grimsey, N., Honer, M., Fingerle, J., Gawrisch, K., Romero, J., Hillard, C. J., Varga, Z. V., van der Stelt, M., Pacher, P., Gertsch, J., McCormick, P. J., Ullmer, C., Oddi, S., Maccarrone, M., Veprintsev, D. B., Nazare, M., Grether, U., Carreira, E. M. 2020; 142 (40): 16953-16964


    Pharmacological modulation of cannabinoid type 2 receptor (CB2R) holds promise for the treatment of numerous conditions, including inflammatory diseases, autoimmune disorders, pain, and cancer. Despite the significance of this receptor, researchers lack reliable tools to address questions concerning the expression and complex mechanism of CB2R signaling, especially in cell-type and tissue-dependent contexts. Herein, we report for the first time a versatile ligand platform for the modular design of a collection of highly specific CB2R fluorescent probes, used successfully across applications, species, and cell types. These include flow cytometry of endogenously expressing cells, real-time confocal microscopy of mouse splenocytes and human macrophages, as well as FRET-based kinetic and equilibrium binding assays. High CB2R specificity was demonstrated by competition experiments in living cells expressing CB2R at native levels. The probes were effectively applied to FACS analysis of microglial cells derived from a mouse model relevant to Alzheimer's disease.

    View details for DOI 10.1021/jacs.0c05587

    View details for Web of Science ID 000579087600010

    View details for PubMedID 32902974

  • Highly Selective, Amine-Derived Cannabinoid Receptor 2 Probes CHEMISTRY-A EUROPEAN JOURNAL Westphal, M., Sarott, R. C., Zirwes, E. A., Osterwald, A., Guba, W., Ullmer, C., Grether, U., Carreira, E. M. 2020; 26 (6): 1380-1387


    The endocannabinoid (eCB) system is implied in various human diseases ranging from central nervous system to autoimmune disorders. Cannabinoid receptor 2 (CB2 R) is an integral component of the eCB system. Yet, the downstream effects elicited by this G protein-coupled receptor upon binding of endogenous or synthetic ligands are insufficiently understood-likely due to the limited arsenal of reliable biological and chemical tools. Herein, we report the design and synthesis of CB2 R-selective cannabinoids along with their in vitro pharmacological characterization (binding and functional studies). They combine structural features of HU-308 and AM841 to give chimeric ligands that emerge as potent CB2 R agonists with high selectivity over the closely related cannabinoid receptor 1 (CB1 R). The synthesis work includes convenient preparation of substituted resorcinols often found in cannabinoids. The utility of the synthetic cannabinoids in this study is showcased by preparation of the most selective high-affinity fluorescent probe for CB2 R to date.

    View details for DOI 10.1002/chem.201904584

    View details for Web of Science ID 000508279100001

    View details for PubMedID 31961047

  • Synthesis of Photoswitchable Delta(9)-Tetrahydrocannabinol Derivatives Enables Optical Control of Cannabinoid Receptor 1 Signaling JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Westphal, M. V., Schafroth, M. A., Sarott, R. C., Imhof, M. A., Bold, C. P., Leippe, P., Dhopeshwarkar, A., Grandner, J. M., Katritch, V., Mackie, K., Trauner, D., Carreira, E. M., Frank, J. A. 2017; 139 (50): 18206-18212


    The cannabinoid receptor 1 (CB1) is an inhibitory G protein-coupled receptor abundantly expressed in the central nervous system. It has rich pharmacology and largely accounts for the recreational use of cannabis. We describe efficient asymmetric syntheses of four photoswitchable Δ9-tetrahydrocannabinol derivatives (azo-THCs) from a central building block 3-Br-THC. Using electrophysiology and a FRET-based cAMP assay, two compounds are identified as potent CB1 agonists that change their effect upon illumination. As such, azo-THCs enable CB1-mediated optical control of inwardly rectifying potassium channels, as well as adenylyl cyclase.

    View details for DOI 10.1021/jacs.7b06456

    View details for Web of Science ID 000418783600019

    View details for PubMedID 29161035

  • Synthesis, characterization and initial evaluation of 5-nitro-1-(trifluoromethyl)-3H-1 lambda(3),2-benziodaoxol-3-one BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY Santschi, N., Sarott, R. C., Otth, E., Kissner, R., Togni, A. 2014; 10: 1-6


    The synthesis of 5-nitro-1-(trifluoromethyl)-3H-1λ(3),2-benziodaoxol-3-one (3), a hypervalent-iodine-based electrophilic trifluoromethylating reagent, is described. Whereas considerations based on cyclic voltammetry and X-ray structural properties would predict an inferior reactivity when compared to the non-nitrated derivative 2, (19)F NMR kinetic studies showed that this new derivative is almost one order of magnitude more reactive. Furthermore, differential scanning calorimetry measurements indicated that, in addition, it is also safer to handle.

    View details for DOI 10.3762/bjoc.10.1

    View details for Web of Science ID 000329819500001

    View details for PubMedID 24454557

    View details for PubMedCentralID PMC3896278