Abstract
Aspartyl aminopeptidase (DNPEP) has been implicated in the control of angiotensin signaling and endosome trafficking, but its precise biologic roles remain incompletely defined. We performed a high-throughput screen of ∼25,000 small molecules to identify inhibitors of DNPEP for use as tools to study its biologic functions. Twenty-three confirmed hits inhibited DNPEP-catalyzed hydrolysis of angiotensin II with micromolar potency. A counter screen against glutamyl aminopeptidase (ENPEP), an enzyme with substrate specificity similar to that of DNPEP, identified eight DNPEP-selective inhibitors. Structure-activity relationships and modeling studies revealed structural features common to the identified inhibitors, including a metal-chelating group and a charged or polar moiety that could interact with portions of the enzyme active site. The compounds identified in this study should be valuable tools for elucidating DNPEP physiology.
Footnotes
- Received April 1, 2014.
- Accepted June 9, 2014.
↵1 Current affiliation: Department of Neurology, College of Medicine, University of Cincinnati, Cincinnati, Ohio.
This work was supported by Case Western Reserve University School of Medicine; and National Institutes of Health [Grant EY008061 (to K.P.)]. K.P. is the John H. Hord Professor of Pharmacology.
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- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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