Membrane transporters

Within the framework of the Swiss National Centre of Competence for Research (NCCR) “Transcure – From Transport Physiology to Therapeutic Approaches” we aim at the discovery of new ligands (inhibitors, modulators, substrate conjugates) for important and potentially disease-relevant biological transporters. More specifically, this work addresses the drug efflux pump ABCG2 (in collaboration with Prof. Kaspar Locher, ETH Zürich), the amino acid transporter LAT1 (SLC7A5) (in collaboration with Proff. Dimitrios Fotiadis and Jürg Gertsch, both at the University of Bern) and mechanisms endocannabinoid transport (in collaboration with Prof. Jürg Gertsch, University of Bern). At the compound level, these projects are not confined to NPs, but also include the modification and optimization of fully synthetic lead structures. Our work on ABCG2 ligands derived from the fungal natural product fumitremorgin C has enabled the first high-resolution structure of liganded ABCG2 by the Locher group. In the endocannabinoid area we have developed sophisticated tool compounds for mechanistic studies of endocannabinoid re-uptake. We have also developed a new total synthesis of the endocannabinoid transport inhibitor guinenseene, a natural product isolated from black pepper, and we have prepared a series of analogs for SAR studies. For LAT1, we have identified novel inhibitors with sub-microM activity (this work is unpublished so far).

Selected reading:

Häfliger, P.; Rubin, M.; Stooss, A.; Gertsch, J.; Charles R.-P.; Graff, J.; Altmann, K.-H.; Dettmer, M. S. The LAT1 inhibitor JPH203 reduces growth of thyroid carcinoma in a fully immunocompetent mouse model. J. Exp. Clin. Cancer Res. 2018, 37, 234. external pagehttps://doi.org/10.1186/s13046-018-0907-z

Jackson, S. M., Manolaridis I., Kowal, I., Zechner, M., Taylor N. M. I., Bause, M., Bauer, S., Bartholomäus, R., Bernhardt G., König, B., Buschauer, A., Stahlberg, H., Altmann, K.-H., Locher, K. P. Structural basis of small-​molecule inhibition of human multidrug transporter ABCG2. Nature Struct. Mol. Biol. 2018, 25, 333-340.

Chicca, A., Nicolussi, S., Bartholomäus, R., Blunder, M., Rey, A. A., Petrucci, V., del Carmen Reynoso-Moreno, I., Viveros-Paredes, J. M., Gens, M. D., Lutz, B., Schioth, H. B., Soeberdt, M., Abels, C., Charles, R.-P., Altmann, K.-H., Gertsch, J. Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake. Proc. Natl. Acad. Sci. U.S.A. 2017, 114, E5006-E5015.

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