ABHD2 inhibitor identified by activity-based protein profiling reduces acrosome reaction
Autor: | Antonius P A Janssen, Ferdinando Scavizzi, Hans den Dulk, Barbara Barboni, Nicola Bernabò, Marcello Raspa, Hermen S. Overkleeft, Bogdan I. Florea, Marc P. Baggelaar, Mario van der Stelt, Mauro Maccarrone, Domenico Fazio |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Male Pyrrolidines Hydrolases Acrosome reaction 01 natural sciences Biochemistry Small Molecule Libraries 03 medical and health sciences Structure-Activity Relationship Piperidines Cell Line Tumor Structure–activity relationship Animals Humans Enzyme Inhibitors Fluorescent Dyes Molecular Structure 010405 organic chemistry Chemistry Acrosome Reaction HEK 293 cells Activity-based proteomics Serine hydrolase Articles General Medicine 3. Good health 0104 chemical sciences Addition/Correction Mice Inbred C57BL 030104 developmental biology HEK293 Cells Cell culture Proteome Lipase inhibitors Molecular Medicine Acrosome |
Zdroj: | ACS Chemical Biology ACS Chemical Biology, 14(10), 2295-2304 |
Popis: | ABHD2 is a serine hydrolase that belongs to the subgroup of the α,β-hydrolase fold-containing proteins, which is involved in virus propagation, immune response, and fertilization. Chemical tools to selectively modulate the activity of ABHD2 in an acute setting are highly desired to investigate its biological role, but are currently lacking. Here, we report a library-versus-library screening using activity-based protein profiling (ABPP) to evaluate in parallel the selectivity and activity of a focused lipase inhibitor library against ABHD2 and a panel of closely related ABHD proteins. This screen resulted in the rapid identification of novel inhibitors for ABHD2. The selectivity of the inhibitor was further investigated in native mouse testis proteome by competitive ABPP, revealing a highly restricted off-target profile. The progesterone-induced acrosome reaction was reduced in a dose-dependent manner by the newly identified inhibitor, which provides further support for the key-role of ABHD2 in the P4-stimulated acrosome reaction. On this basis, the ABHD2 inhibitor is an excellent starting point for further optimization of ABHD2 inhibitors that can modulate sperm fertility and may lead to novel contraceptives. |
Databáze: | OpenAIRE |
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