Structure-Guided, Single-Point Modifications in the Phosphinic Dipeptide Structure Yield Highly Potent and Selective Inhibitors of Neutral Aminopeptidases
Abstract
Seven crystal structures of alanyl aminopeptidase from Neisseria meningitides (the etiological agent of meningitis, NmAPN) complexed with organophosphorus compounds were resolved to determine the optimal inhibitor–enzyme interactions. The enantiomeric phosphonic acid analogs of Leu and hPhe, which correspond to the P1 amino acid residues of well-processed substrates, were used to assess the impact of the absolute configuration and the stereospecific hydrogen bond network formed between the aminophosphonate polar head and the active site residues on the binding affinity. For the hPhe analog, an imperfect stereochemical complementarity could be overcome by incorporating an appropriate P1 side chain. The constitution of P1'-extended structures was rationally designed and the lead, phosphinic dipeptide hPhePψ[CH2]Phe, was modified in a single position. Introducing a heteroatom/heteroatom-based fragment to either the P1 or P1' residue required new synthetic pathways. The compounds in the refined structure were low nanomolar and subnanomolar inhibitors of N. meningitides, porcine and human APNs, and the reference leucine aminopeptidase (LAP). The unnatural phosphinic dipeptide analogs exhibited a high affinity for monozinc APNs associated with a reasonable selectivity versus dizinc LAP. In conclusion, another set of crystal structures containing the NmAPN dipeptide ligand were used to verify and to confirm the predicted binding modes; furthermore,more »
- Authors:
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); Polish National Science Centre (NCN)
- OSTI Identifier:
- 1261141
- Grant/Contract Number:
- AC02-06CH11357; GM094585; 2013/09/B/ST5/00090
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Medicinal Chemistry
- Additional Journal Information:
- Journal Volume: 57; Journal Issue: 19; Journal ID: ISSN 0022-2623
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Vassiliou, Stamatia, Węglarz-Tomczak, Ewelina, Berlicki, Łukasz, Pawełczak, Małgorzata, Nocek, Bogusław, Mulligan, Rory, Joachimiak, Andrzej, and Mucha, Artur. Structure-Guided, Single-Point Modifications in the Phosphinic Dipeptide Structure Yield Highly Potent and Selective Inhibitors of Neutral Aminopeptidases. United States: N. p., 2014.
Web. doi:10.1021/jm501071f.
Vassiliou, Stamatia, Węglarz-Tomczak, Ewelina, Berlicki, Łukasz, Pawełczak, Małgorzata, Nocek, Bogusław, Mulligan, Rory, Joachimiak, Andrzej, & Mucha, Artur. Structure-Guided, Single-Point Modifications in the Phosphinic Dipeptide Structure Yield Highly Potent and Selective Inhibitors of Neutral Aminopeptidases. United States. https://doi.org/10.1021/jm501071f
Vassiliou, Stamatia, Węglarz-Tomczak, Ewelina, Berlicki, Łukasz, Pawełczak, Małgorzata, Nocek, Bogusław, Mulligan, Rory, Joachimiak, Andrzej, and Mucha, Artur. Thu .
"Structure-Guided, Single-Point Modifications in the Phosphinic Dipeptide Structure Yield Highly Potent and Selective Inhibitors of Neutral Aminopeptidases". United States. https://doi.org/10.1021/jm501071f. https://www.osti.gov/servlets/purl/1261141.
@article{osti_1261141,
title = {Structure-Guided, Single-Point Modifications in the Phosphinic Dipeptide Structure Yield Highly Potent and Selective Inhibitors of Neutral Aminopeptidases},
author = {Vassiliou, Stamatia and Węglarz-Tomczak, Ewelina and Berlicki, Łukasz and Pawełczak, Małgorzata and Nocek, Bogusław and Mulligan, Rory and Joachimiak, Andrzej and Mucha, Artur},
abstractNote = {Seven crystal structures of alanyl aminopeptidase from Neisseria meningitides (the etiological agent of meningitis, NmAPN) complexed with organophosphorus compounds were resolved to determine the optimal inhibitor–enzyme interactions. The enantiomeric phosphonic acid analogs of Leu and hPhe, which correspond to the P1 amino acid residues of well-processed substrates, were used to assess the impact of the absolute configuration and the stereospecific hydrogen bond network formed between the aminophosphonate polar head and the active site residues on the binding affinity. For the hPhe analog, an imperfect stereochemical complementarity could be overcome by incorporating an appropriate P1 side chain. The constitution of P1'-extended structures was rationally designed and the lead, phosphinic dipeptide hPhePψ[CH2]Phe, was modified in a single position. Introducing a heteroatom/heteroatom-based fragment to either the P1 or P1' residue required new synthetic pathways. The compounds in the refined structure were low nanomolar and subnanomolar inhibitors of N. meningitides, porcine and human APNs, and the reference leucine aminopeptidase (LAP). The unnatural phosphinic dipeptide analogs exhibited a high affinity for monozinc APNs associated with a reasonable selectivity versus dizinc LAP. In conclusion, another set of crystal structures containing the NmAPN dipeptide ligand were used to verify and to confirm the predicted binding modes; furthermore, novel contacts, which were promising for inhibitor development, were identified, including a π–π stacking interaction between a pyridine ring and Tyr372.},
doi = {10.1021/jm501071f},
journal = {Journal of Medicinal Chemistry},
number = 19,
volume = 57,
place = {United States},
year = {Thu Oct 09 00:00:00 EDT 2014},
month = {Thu Oct 09 00:00:00 EDT 2014}
}
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Neutral metalloaminopeptidases APN and MetAP2 as newly discovered anticancer molecular targets of actinomycin D and its simple analogs
journal, June 2018
- Węglarz-Tomczak, Ewelina; Talma, Michał; Giurg, Mirosław
- Oncotarget, Vol. 9, Issue 50
Phosphonic Analogues of Phenylglycine as Inhibitors of Aminopeptidases: Comparison of Porcine Aminopeptidase N, Bovine Leucine Aminopeptidase and Aminopeptidase from Barley Seeds
journal, May 2019
- Wanat, Weromika; Talma, Michal; Pawelczak, Malgorzata
- Preprints
Aminobenzosuberone Scaffold as a Modular Chemical Tool for the Inhibition of Therapeutically Relevant M1 Aminopeptidases
journal, October 2018
- Salomon, Emmanuel; Schmitt, Marjorie; Marapaka, Anil
- Molecules, Vol. 23, Issue 10