Optical Control of Proteasomal Protein Degradation with a Photoswitchable Lipopeptide

Author:

Morstein Johannes12,Amatuni Alexander3,Shuster Anton3,Kuttenlochner Wolfgang4,Ko Tongil25,Abegg Daniel6,Groll Michael4,Adibekian Alexander6,Renata Hans7,Trauner Dirk H.25ORCID

Affiliation:

1. Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute University of California San Francisco CA-94158 USA

2. Department of Chemistry New York University New York NY-10003 USA

3. Skaggs Doctoral Program in the Chemical and Biological Sciences Scripps Research La Jolla CA-92037 USA

4. Technical University of Munich TUM School of Natural Sciences Department of Bioscience, Center for Protein Assemblies, Chair of Biochemistry Ernst-Otto-Fischer-Str. 8 85748 Garching Germany

5. Department of Chemistry University of Pennsylvania Philadelphia PA-19104 USA

6. Department of Chemistry University of Illinois Chicago Chicago IL-60607 USA

7. Department of Chemistry BioScience Research Collaborative Rice University Houston TX-77005 USA

Abstract

AbstractPhotolipids have emerged as attractive tools for the optical control of lipid functions. They often contain an azobenzene photoswitch that imparts a cis double‐bond upon irradiation. Herein, we present the application of photoswitching to a lipidated natural product, the potent proteasome inhibitor cepafungin I. Several azobenzene‐containing lipids were attached to the cyclopeptide core, yielding photoswitchable derivatives. Most notably, PhotoCep4 exhibited a 10‐fold higher cellular potency in its light‐induced cis‐form, matching the potency of natural cepafungin I. The length of the photolipid tail and distal positioning of the azobenzene photoswitch with respect to the macrocycle is critical for this activity. In a proteome‐wide experiment, light‐triggered PhotoCep4 modulation showed high overlap with constitutively active cepafungin I. The mode of action was studied using crystallography and revealed an identical binding of the cyclopeptide in comparison to cepafungin I, suggesting that differences in their cellular activity originate from switching the tail structure. The photopharmacological approach described herein could be applicable to many other natural products as lipid conjugation is common and often necessary for potent activity. Such lipids are often introduced late in synthetic routes, enabling facile chemical modifications.

Funder

National Cancer Institute

National Institutes of Health

Deutsche Forschungsgemeinschaft

Publisher

Wiley

Subject

General Medicine

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