title: Identification and characterization of novel inhibitors of Mammalian aspartyl aminopeptidase.
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.
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (Y.C., K.O., X.L., J.Z., M.G., K.P., P.D.K.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (H.T., W.S., R.P.).
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (Y.C., K.O., X.L., J.Z., M.G., K.P., P.D.K.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (H.T., W.S., R.P.).
authors.forename: Hong
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (Y.C., K.O., X.L., J.Z., M.G., K.P., P.D.K.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (H.T., W.S., R.P.).
authors.forename: William
authors.initials: W
authors.lastname: Seibel
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (Y.C., K.O., X.L., J.Z., M.G., K.P., P.D.K.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (H.T., W.S., R.P.).
authors.forename: Ruben
authors.initials: R
authors.lastname: Papoian
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (Y.C., K.O., X.L., J.Z., M.G., K.P., P.D.K.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (H.T., W.S., R.P.).
authors.forename: Ki
authors.initials: K
authors.lastname: Oh
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (Y.C., K.O., X.L., J.Z., M.G., K.P., P.D.K.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (H.T., W.S., R.P.).
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (Y.C., K.O., X.L., J.Z., M.G., K.P., P.D.K.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (H.T., W.S., R.P.).
authors.forename: Jianye
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (Y.C., K.O., X.L., J.Z., M.G., K.P., P.D.K.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (H.T., W.S., R.P.).
authors.forename: Marcin
authors.initials: M
authors.lastname: Golczak
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (Y.C., K.O., X.L., J.Z., M.G., K.P., P.D.K.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (H.T., W.S., R.P.) kxp65@case.edu pdk7@case.edu.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (Y.C., K.O., X.L., J.Z., M.G., K.P., P.D.K.); and Drug Discovery Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio (H.T., W.S., R.P.) kxp65@case.edu pdk7@case.edu.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Kiser
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D020134:Catalytic Domain / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D043384:Glutamyl Aminopeptidase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D008322:Mammals; D061987:Sf9 Cells; D018411:Spodoptera; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D000804:Angiotensin II; D043384:Glutamyl Aminopeptidase