Short Photoswitchable Ceramides Enable Optical Control of Apoptosis

Creators: Morstein, Johannes^{1, 2}; Kol, Matthijs; Novak, Alexander J. E.; Feng, Suihan; Khayyo, Shadi; Hinnah, Konstantin; Li-Purcell, Nasi; Pan, Grace; Williams, Benjamin M.; Riezman, Howard; Atilla-Gokcumen, G. Ekin; Holthuis, Joost C. M.; Trauner, Dirk

1. New York University
2. California Institute of Technology

Abstract

We report short ceramide analogs that can be activated with light and further functionalized using azide–alkyne click chemistry. These molecules, termed scaCers, exhibit increased cell permeability compared to their long-chain analogs as demonstrated using mass spectrometry and imaging. Notably, scaCers enable optical control of apoptosis, which is not observed with long-chain variants. Additionally, they function as photoswitchable substrates for sphingomyelin synthase 2 (SMS2), exhibiting inverted light-dependence compared to their extended analogs.

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Acknowledgement

We thank New York University for financial support. NMR spectra were acquired using the TCI cryoprobe supported by the NIH (OD016343). J.M. and K.H. thank the German Academic Scholarship Foundation for a fellowship, and J.M. and A.J.N. thank the New York University for a MacCracken Ph.D. fellowship. J.M. thanks New York University for a Margaret and Herman Sokol fellowship, and the NCI for a F99/K00 award (1F99CA253758-01). J.C.M.H. acknowledges support from the Deutsche Forschungsgemeinschaft (SFB944-P14 and HO3539/1-1). G.E.A.G. acknowledges the support from the National Science Foundation (MCB1817468). G.P. thanks New York University for a Dean’s Undergraduate Research Fund (DURF) Grant.

Additional Information

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschembio.0c00823.

Experimental details, NMR spectra, photophysical characterization (PDF)

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