ABHD2 Inhibitor Identified by Activity-Based Protein Profiling Reduces Acrosome Reaction

Abstract

ABHD2\nis a serine hydrolase that belongs to the subgroup of the\nα,β-hydrolase fold-containing proteins, which is involved\nin virus propagation, immune response, and fertilization. Chemical\ntools to selectively modulate the activity of ABHD2 in an acute setting\nare highly desired to investigate its biological role, but are currently\nlacking. Here, we report a library-versus-library screening using\nactivity-based protein profiling (ABPP) to evaluate in parallel the\nselectivity and activity of a focused lipase inhibitor library against\nABHD2 and a panel of closely related ABHD proteins. This screen resulted\nin the rapid identification of novel inhibitors for ABHD2. The selectivity\nof the inhibitor was further investigated in native mouse testis proteome\nby competitive ABPP, revealing a highly restricted off-target profile.\nThe progesterone-induced acrosome reaction was reduced in a dose-dependent\nmanner by the newly identified inhibitor, which provides further support\nfor the key-role of ABHD2 in the P4-stimulated acrosome reaction.\nOn this basis, the ABHD2 inhibitor is an excellent starting point\nfor further optimization of ABHD2 inhibitors that can modulate sperm\nfertility and may lead to novel contraceptives.