TY - JOUR
T1 - Discovery of small-molecule enzyme activators by activity-based protein profiling
AU - Kok, Bernard P.
AU - Ghimire, Srijana
AU - Kim, Woojoo
AU - Chatterjee, Shreyosree
AU - Johns, Tyler
AU - Kitamura, Seiya
AU - Eberhardt, Jerome
AU - Ogasawara, Daisuke
AU - Xu, Janice
AU - Sukiasyan, Ara
AU - Kim, Sean M.
AU - Godio, Cristina
AU - Bittencourt, Julia M.
AU - Cameron, Michael
AU - Galmozzi, Andrea
AU - Forli, Stefano
AU - Wolan, Dennis W.
AU - Cravatt, Benjamin F.
AU - Boger, Dale L.
AU - Saez, Enrique
N1 - Funding Information:
We thank C. Moore and A. Rheingold of the Crystallography Facility at the University of California, San Diego for X-ray structure determinations of 4, 12, 34, 37 and 78, C. Vernochet, T.V. Magee and C. Hong at Pfizer for compounds C11 and C12, and M. Petrassi at Calibr for discussions. This work was supported by National Institutes of Health grant nos. DA015648 (to D.L.B.), GM069832 (to S.F.), DK099810 (to E.S. and B.F.C.) and DK114785 (to E.S. and B.F.C.). B.P.K. was supported in part by fellowship no. 15POST25100007 from the American Heart Association.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Activity-based protein profiling (ABPP) has been used extensively to discover and optimize selective inhibitors of enzymes. Here, we show that ABPP can also be implemented to identify the converse—small-molecule enzyme activators. Using a kinetically controlled, fluorescence polarization-ABPP assay, we identify compounds that stimulate the activity of LYPLAL1—a poorly characterized serine hydrolase with complex genetic links to human metabolic traits. We apply ABPP-guided medicinal chemistry to advance a lead into a selective LYPLAL1 activator suitable for use in vivo. Structural simulations coupled to mutational, biochemical and biophysical analyses indicate that this compound increases LYPLAL1’s catalytic activity likely by enhancing the efficiency of the catalytic triad charge-relay system. Treatment with this LYPLAL1 activator confers beneficial effects in a mouse model of diet-induced obesity. These findings reveal a new mode of pharmacological regulation for this large enzyme family and suggest that ABPP may aid discovery of activators for additional enzyme classes. [Figure not available: see fulltext.].
AB - Activity-based protein profiling (ABPP) has been used extensively to discover and optimize selective inhibitors of enzymes. Here, we show that ABPP can also be implemented to identify the converse—small-molecule enzyme activators. Using a kinetically controlled, fluorescence polarization-ABPP assay, we identify compounds that stimulate the activity of LYPLAL1—a poorly characterized serine hydrolase with complex genetic links to human metabolic traits. We apply ABPP-guided medicinal chemistry to advance a lead into a selective LYPLAL1 activator suitable for use in vivo. Structural simulations coupled to mutational, biochemical and biophysical analyses indicate that this compound increases LYPLAL1’s catalytic activity likely by enhancing the efficiency of the catalytic triad charge-relay system. Treatment with this LYPLAL1 activator confers beneficial effects in a mouse model of diet-induced obesity. These findings reveal a new mode of pharmacological regulation for this large enzyme family and suggest that ABPP may aid discovery of activators for additional enzyme classes. [Figure not available: see fulltext.].
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U2 - 10.1038/s41589-020-0555-4
DO - 10.1038/s41589-020-0555-4
M3 - Article
C2 - 32514184
AN - SCOPUS:85086156930
SN - 1552-4450
VL - 16
SP - 997
EP - 1005
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 9
ER -
