Pepstatin-Based Probes for Photoaffinity Labeling of Aspartic Proteases and Application to Target Identification

Chen S, Liang C, Li H, Yu W, Prothiwa M, Kopczynski D, Loroch S, Fransen M, Verhelst SH (2023)

Publication Type: Journal article

Publication year: 2023

Journal

ACS Chemical Biology American Chemical Society

Book Volume: 18

Pages Range: 686-692

Journal Issue: 4

DOI: 10.1021/acschembio.2c00946

Abstract

Aspartic proteases are a small class of proteases implicated in a wide variety of human diseases. Covalent chemical probes for photoaffinity labeling (PAL) of these proteases are underdeveloped. We here report a full on-resin synthesis of clickable PAL probes based on the natural product inhibitor pepstatin incorporating a minimal diazirine reactive group. The position of this group in the inhibitor determines the labeling efficiency. The most effective probes sensitively detect cathepsin D, a biomarker for breast cancer, in cell lysates. Moreover, through chemical proteomics experiments and deep learning algorithms, we identified sequestosome-1, an important player in autophagy, as a direct interaction partner and substrate of cathepsin D.

Involved external institutions

Leibniz-Institut für Analytische Wissenschaften / Leibniz Institute for Analytical Sciences (ISAS) DE Germany (DE) Julius-Maximilians-Universität Würzburg DE Germany (DE) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven BE Belgium (BE) Universität Wien / University of Vienna AT Austria (AT)

How to cite

APA:

Chen, S., Liang, C., Li, H., Yu, W., Prothiwa, M., Kopczynski, D.,... Verhelst, S.H. (2023). Pepstatin-Based Probes for Photoaffinity Labeling of Aspartic Proteases and Application to Target Identification. ACS Chemical Biology, 18(4), 686-692. https://doi.org/10.1021/acschembio.2c00946

MLA:

Chen, Suyuan, et al. "Pepstatin-Based Probes for Photoaffinity Labeling of Aspartic Proteases and Application to Target Identification." ACS Chemical Biology 18.4 (2023): 686-692.

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