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Chemoproteomic screen to identify rabeprazole off-targets in intact HEK293 MSR cells

ABSTRACT: Proton pump inhibitors (PPIs) have become top-selling drugs worldwide. They are prodrugs activated by protonation in highly acidic environments. They inhibit stomach acid secretion by covalently modifying the gastric H+/K+-ATPase. However, little is known about alternative activation mechanisms and target proteins in non-acidic environments. Employing a chemoproteomic approach in living cells, we find rabeprazole to form covalent conjugates with numerous zinc-binding proteins. We show that one of the main target proteins, density-regulated protein (DENR), is conjugated to rabeprazole through a cysteine residue forming part of the zinc-binding site. We propose that zinc acts as a Lewis acid, obviating the need for low pH, to promote the activation of PPIs in non-acidic environments. Our findings may aid the understanding of secondary drug effects and/or the repurposing of PPIs.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hek-293 Cell, Kidney Cell

SUBMITTER: Frank Stein

LAB HEAD: Tobias P Dick

PROVIDER: PXD048457 | Pride | 2025-01-30

REPOSITORIES: Pride

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	F088920.dat	Other
	F088923.dat	Other
	F088926.dat	Other
	P1122_PH_TM_Zelda_191105_P1122_PH_TM_n1_R1_T_results_20201218_1108_peptides.txt	Txt
	P1122_PH_TM_Zelda_191105_P1122_PH_TM_n1_R1_T_results_20201218_1108_proteins.txt	Txt

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