- Identification and characterization of novel inhibitors of mammalian aspartyl aminopeptidase
-
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. Copyright
- Chen, Yuanyuan,Tang, Hong,Seibel, William,Papoian, Ruben,Oh, Ki,Li, Xiaoyu,Zhang, Jianye,Golczak, Marcin,Palczewski, Krzysztof,Kiser, Philip D.
-
p. 231 - 242
(2014/10/15)
-
