PT - JOURNAL ARTICLE AU - Yuanyuan Chen AU - Hong Tang AU - William Seibel AU - Ruben Papoian AU - Ki Oh AU - Xiaoyu Li AU - Jianye Zhang AU - Marcin Golczak AU - Krzysztof Palczewski AU - Philip Kiser TI - Identification and Characterization of Novel Inhibitors of Mammalian Aspartyl Aminopeptidase AID - 10.1124/mol.114.093070 DP - 2014 Jan 01 TA - Molecular Pharmacology PG - mol.114.093070 4099 - http://molpharm.aspetjournals.org/content/early/2014/06/09/mol.114.093070.short 4100 - http://molpharm.aspetjournals.org/content/early/2014/06/09/mol.114.093070.full AB - Aspartyl aminopeptidase (DNPEP) has been implicated in the control of angiotensin signaling and endosome trafficking, but its precise biological roles remains 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 biological 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.