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Molecular Pharmacology

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Research ArticleArticle

Identification and Characterization of Novel Inhibitors of Mammalian Aspartyl Aminopeptidase

Yuanyuan Chen, Hong Tang, William Seibel, Ruben Papoian, Ki Oh, Xiaoyu Li, Jianye Zhang, Marcin Golczak, Krzysztof Palczewski and Philip D. Kiser
Molecular Pharmacology August 2014, 86 (2) 231-242; DOI: https://doi.org/10.1124/mol.114.093070
Yuanyuan Chen
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.)
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Hong Tang
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.)
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William Seibel
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.)
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Ruben Papoian
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.)
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Ki Oh
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.)
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Xiaoyu Li
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.)
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Jianye Zhang
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.)
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Marcin Golczak
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.)
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Krzysztof Palczewski
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.)
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Philip D. Kiser
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.)
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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.

  • dx.doi.org/10.1124/mol.114.093070.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (2)
Molecular Pharmacology
Vol. 86, Issue 2
1 Aug 2014
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Research ArticleArticle

Discovery of Small-Molecule DNPEP Inhibitors

Yuanyuan Chen, Hong Tang, William Seibel, Ruben Papoian, Ki Oh, Xiaoyu Li, Jianye Zhang, Marcin Golczak, Krzysztof Palczewski and Philip D. Kiser
Molecular Pharmacology August 1, 2014, 86 (2) 231-242; DOI: https://doi.org/10.1124/mol.114.093070

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Research ArticleArticle

Discovery of Small-Molecule DNPEP Inhibitors

Yuanyuan Chen, Hong Tang, William Seibel, Ruben Papoian, Ki Oh, Xiaoyu Li, Jianye Zhang, Marcin Golczak, Krzysztof Palczewski and Philip D. Kiser
Molecular Pharmacology August 1, 2014, 86 (2) 231-242; DOI: https://doi.org/10.1124/mol.114.093070
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