Development of Novel Peptide-Based Michael Acceptors Targeting Rhodesain and Falcipain-2 for the Treatment of Neglected Tropical Diseases (NTDs)
- Publikationstyp:
- Zeitschriftenaufsatz
- Metadaten:
-
- Autoren
- Santo Previti
- Roberta Ettari
- Sandro Cosconati
- Giorgio Arnendola
- Khawla Chouchene
- Annika Wagner
- Ute A Hellmich
- Kathrin Ulrich
- R Luise Krauth-Siegel
- Peter R Wich
- Ira Schmid
- Tanja Schirmeister
- Jiri Gut
- Philip J Rosenthal
- Silvana Grasso
- Maria Zappala
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000408598500008&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1021/acs.jmedchem.7b00405
- eISSN
- 1520-4804
- Externe Identifier
- Clarivate Analytics Document Solution ID: FF0NN
- PubMed Identifier: 28763614
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 16
- Zeitschrift
- JOURNAL OF MEDICINAL CHEMISTRY
- Paginierung
- 6911 - 6923
- Datum der Veröffentlichung
- 2017
- Status
- Published
- Titel
- Development of Novel Peptide-Based Michael Acceptors Targeting Rhodesain and Falcipain-2 for the Treatment of Neglected Tropical Diseases (NTDs)
- Sub types
- Article
- Ausgabe der Zeitschrift
- 60
Datenquelle: Web of Science (Lite)
- Andere Metadatenquellen:
-
- Autoren
- Santo Previti
- Roberta Ettari
- Sandro Cosconati
- Giorgio Amendola
- Khawla Chouchene
- Annika Wagner
- Ute A Hellmich
- Kathrin Ulrich
- R Luise Krauth-Siegel
- Peter R Wich
- Ira Schmid
- Tanja Schirmeister
- Jiri Gut
- Philip J Rosenthal
- Silvana Grasso
- Maria Zappalà
- DOI
- 10.1021/acs.jmedchem.7b00405
- eISSN
- 1520-4804
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 16
- Zeitschrift
- Journal of Medicinal Chemistry
- Sprache
- en
- Online publication date
- 2017
- Paginierung
- 6911 - 6923
- Datum der Veröffentlichung
- 2017
- Status
- Published
- Herausgeber
- American Chemical Society (ACS)
- Herausgeber URL
- http://dx.doi.org/10.1021/acs.jmedchem.7b00405
- Datum der Datenerfassung
- 2023
- Titel
- Development of Novel Peptide-Based Michael Acceptors Targeting Rhodesain and Falcipain-2 for the Treatment of Neglected Tropical Diseases (NTDs)
- Ausgabe der Zeitschrift
- 60
Datenquelle: Crossref
- Abstract
- This paper describes the development of a class of peptide-based inhibitors as novel antitrypanosomal and antimalarial agents. The inhibitors are based on a characteristic peptide sequence for the inhibition of the cysteine proteases rhodesain of Trypanosoma brucei rhodesiense and falcipain-2 of Plasmodium falciparum. We exploited the reactivity of novel unsaturated electrophilic functions such as vinyl-sulfones, -ketones, -esters, and -nitriles. The Michael acceptors inhibited both rhodesain and falcipain-2, at nanomolar and micromolar levels, respectively. In particular, the vinyl ketone 3b has emerged as a potent rhodesain inhibitor (k<sub>2nd</sub> = 67 × 10<sup>6</sup> M<sup>-1</sup> min<sup>-1</sup>), endowed with a picomolar binding affinity (K<sub>i</sub> = 38 pM), coupled with a single-digit micromolar activity against Trypanosoma brucei brucei (EC<sub>50</sub> = 2.97 μM), thus being considered as a novel lead compound for the discovery of novel effective antitrypanosomal agents.
- Addresses
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina , Viale Annunziata, 98168 Messina, Italy.
- Autoren
- Santo Previti
- Roberta Ettari
- Sandro Cosconati
- Giorgio Amendola
- Khawla Chouchene
- Annika Wagner
- Ute A Hellmich
- Kathrin Ulrich
- R Luise Krauth-Siegel
- Peter R Wich
- Ira Schmid
- Tanja Schirmeister
- Jiri Gut
- Philip J Rosenthal
- Silvana Grasso
- Maria Zappalà
- DOI
- 10.1021/acs.jmedchem.7b00405
- eISSN
- 1520-4804
- Externe Identifier
- PubMed Identifier: 28763614
- Funding acknowledgements
- Universit? degli Studi di Messina:
- Zentrum f?r Biomolekulare Magnetische Resonanzspektroskopie, Goethe-Universit?t Frankfurt am Main:
- Carl-Zeiss-Stiftung:
- Open access
- false
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 16
- Zeitschrift
- Journal of medicinal chemistry
- Schlüsselwörter
- Hela Cells
- Humans
- Plasmodium falciparum
- Trypanosoma brucei brucei
- Malaria
- Trypanosomiasis, African
- Carbamates
- Cysteine Endopeptidases
- Phenylalanine
- Dipeptides
- Cysteine Proteinase Inhibitors
- Antimalarials
- Trypanocidal Agents
- Structure-Activity Relationship
- Stereoisomerism
- Hydrogen Bonding
- Molecular Dynamics Simulation
- Cathepsin L
- Neglected Diseases
- Molecular Docking Simulation
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2017
- Paginierung
- 6911 - 6923
- Datum der Veröffentlichung
- 2017
- Status
- Published
- Datum der Datenerfassung
- 2017
- Titel
- Development of Novel Peptide-Based Michael Acceptors Targeting Rhodesain and Falcipain-2 for the Treatment of Neglected Tropical Diseases (NTDs).
- Sub types
- Research Support, Non-U.S. Gov't
- Journal Article
- Ausgabe der Zeitschrift
- 60
Datenquelle: Europe PubMed Central
- Abstract
- This paper describes the development of a class of peptide-based inhibitors as novel antitrypanosomal and antimalarial agents. The inhibitors are based on a characteristic peptide sequence for the inhibition of the cysteine proteases rhodesain of Trypanosoma brucei rhodesiense and falcipain-2 of Plasmodium falciparum. We exploited the reactivity of novel unsaturated electrophilic functions such as vinyl-sulfones, -ketones, -esters, and -nitriles. The Michael acceptors inhibited both rhodesain and falcipain-2, at nanomolar and micromolar levels, respectively. In particular, the vinyl ketone 3b has emerged as a potent rhodesain inhibitor (k2nd = 67 × 106 M-1 min-1), endowed with a picomolar binding affinity (Ki = 38 pM), coupled with a single-digit micromolar activity against Trypanosoma brucei brucei (EC50 = 2.97 μM), thus being considered as a novel lead compound for the discovery of novel effective antitrypanosomal agents.
- Autoren
- Santo Previti
- Roberta Ettari
- Sandro Cosconati
- Giorgio Amendola
- Khawla Chouchene
- Annika Wagner
- Ute A Hellmich
- Kathrin Ulrich
- R Luise Krauth-Siegel
- Peter R Wich
- Ira Schmid
- Tanja Schirmeister
- Jiri Gut
- Philip J Rosenthal
- Silvana Grasso
- Maria Zappalà
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/28763614
- DOI
- 10.1021/acs.jmedchem.7b00405
- eISSN
- 1520-4804
- Ausgabe der Veröffentlichung
- 16
- Zeitschrift
- J Med Chem
- Schlüsselwörter
- Antimalarials
- Carbamates
- Cathepsin L
- Cysteine Endopeptidases
- Cysteine Proteinase Inhibitors
- Dipeptides
- HeLa Cells
- Humans
- Hydrogen Bonding
- Malaria
- Molecular Docking Simulation
- Molecular Dynamics Simulation
- Neglected Diseases
- Phenylalanine
- Plasmodium falciparum
- Stereoisomerism
- Structure-Activity Relationship
- Trypanocidal Agents
- Trypanosoma brucei brucei
- Trypanosomiasis, African
- Sprache
- eng
- Country
- United States
- Paginierung
- 6911 - 6923
- Datum der Veröffentlichung
- 2017
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2017
- Titel
- Development of Novel Peptide-Based Michael Acceptors Targeting Rhodesain and Falcipain-2 for the Treatment of Neglected Tropical Diseases (NTDs).
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 60
Datenquelle: PubMed
- Autoren
- Santo Previti
- Roberta Ettari
- Sandro Cosconati
- Giorgio Amendola
- Khawla Chouchene
- Annika Wagner
- Ute A Hellmich
- Kathrin Ulrich
- R Luise Krauth-Siegel
- Peter R Wich
- others
- Zeitschrift
- Journal of Medicinal Chemistry
- Artikelnummer
- 16
- Paginierung
- 6911 - 6923
- Datum der Veröffentlichung
- 2017
- Herausgeber
- ACS Publications
- Datum der Datenerfassung
- 2021
- Titel
- Development of Novel Peptide-Based Michael Acceptors Targeting Rhodesain and Falcipain-2 for the Treatment of Neglected Tropical Diseases (NTDs)
- Sub types
- article
- Ausgabe der Zeitschrift
- 60
Datenquelle: Manual
- Beziehungen:
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