Development of Novel Benzodiazepine-Based Peptidomimetics as Inhibitors of Rhodesain from Trypanosoma brucei rhodesiense
- Publikationstyp:
- Zeitschriftenaufsatz
- Metadaten:
-
- Autoren
- Carla Di Chio
- Santo Previti
- Giorgio Amendola
- Sandro Cosconati
- Tanja Schirmeister
- Maria Zappala
- Roberta Ettari
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000530076000001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1002/cmdc.202000158
- eISSN
- 1860-7187
- Externe Identifier
- Clarivate Analytics Document Solution ID: LU1NK
- PubMed Identifier: 32329206
- ISSN
- 1860-7179
- Ausgabe der Veröffentlichung
- 11
- Zeitschrift
- CHEMMEDCHEM
- Schlüsselwörter
- benzodiazepine scaffold
- human African trypanosomiasis
- Michael acceptors
- rhodesain
- Trypanosoma brucei
- peptidomimetics
- Paginierung
- 995 - 1001
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Titel
- Development of Novel Benzodiazepine-Based Peptidomimetics as Inhibitors of Rhodesain from <i>Trypanosoma brucei rhodesiense</i>
- Sub types
- Article
- Ausgabe der Zeitschrift
- 15
Datenquelle: Web of Science (Lite)
- Andere Metadatenquellen:
-
- Abstract
- <jats:title>Abstract</jats:title><jats:p>Starting from the reversible rhodesain inhibitors <jats:bold>1 a</jats:bold>–<jats:bold>c</jats:bold>, which have <jats:italic>K</jats:italic><jats:sub>i</jats:sub> values towards the target protease in the low‐micromolar range, we have designed a series of peptidomimetics, <jats:bold>2 a</jats:bold>–<jats:bold>g</jats:bold>, that contain a benzodiazepine scaffold as a β‐turn mimetic; they are characterized by a specific peptide sequence for the inhibition of rhodesain. Considering that irreversible inhibition is strongly desirable in the case of a parasitic target, a vinyl ester moiety acting as Michael‐acceptor was introduced as the warhead; this portion was functionalized in order to evaluate the size of corresponding enzyme pocket that could accommodate this substituent. With this investigation, we identified an irreversible rhodesain inhibitor (i. e., <jats:bold>2 g</jats:bold>) with a <jats:italic>k</jats:italic><jats:sub>2nd</jats:sub> value of 90 000 M<jats:sup>−1</jats:sup> min<jats:sup>−1</jats:sup> that showed antitrypanosomal activity in the low‐micromolar range (EC<jats:sub>50</jats:sub>=1.25 μM), this may be considered a promising lead compound in the drug‐discovery process for treating human African trypanosomiasis (HAT).</jats:p>
- Autoren
- Carla Di Chio
- Santo Previti
- Giorgio Amendola
- Sandro Cosconati
- Tanja Schirmeister
- Maria Zappalà
- Roberta Ettari
- DOI
- 10.1002/cmdc.202000158
- eISSN
- 1860-7187
- ISSN
- 1860-7179
- Ausgabe der Veröffentlichung
- 11
- Zeitschrift
- ChemMedChem
- Sprache
- en
- Online publication date
- 2020
- Paginierung
- 995 - 1001
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Herausgeber
- Wiley
- Herausgeber URL
- http://dx.doi.org/10.1002/cmdc.202000158
- Datum der Datenerfassung
- 2023
- Titel
- Development of Novel Benzodiazepine‐Based Peptidomimetics as Inhibitors of Rhodesain from <i>Trypanosoma brucei rhodesiense</i>
- Ausgabe der Zeitschrift
- 15
Datenquelle: Crossref
- Abstract
- Starting from the reversible rhodesain inhibitors 1 a-c, which have K<sub>i</sub> values towards the target protease in the low-micromolar range, we have designed a series of peptidomimetics, 2 a-g, that contain a benzodiazepine scaffold as a β-turn mimetic; they are characterized by a specific peptide sequence for the inhibition of rhodesain. Considering that irreversible inhibition is strongly desirable in the case of a parasitic target, a vinyl ester moiety acting as Michael-acceptor was introduced as the warhead; this portion was functionalized in order to evaluate the size of corresponding enzyme pocket that could accommodate this substituent. With this investigation, we identified an irreversible rhodesain inhibitor (i. e., 2 g) with a k<sub>2nd</sub> value of 90 000 M<sup>-1</sup> min<sup>-1</sup> that showed antitrypanosomal activity in the low-micromolar range (EC<sub>50</sub> =1.25 μM), this may be considered a promising lead compound in the drug-discovery process for treating human African trypanosomiasis (HAT).
- Addresses
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Annunziata, 98168, Messina, Italy.
- Autoren
- Carla Di Chio
- Santo Previti
- Giorgio Amendola
- Sandro Cosconati
- Tanja Schirmeister
- Maria Zappalà
- Roberta Ettari
- DOI
- 10.1002/cmdc.202000158
- eISSN
- 1860-7187
- Externe Identifier
- PubMed Identifier: 32329206
- Open access
- false
- ISSN
- 1860-7179
- Ausgabe der Veröffentlichung
- 11
- Zeitschrift
- ChemMedChem
- Schlüsselwörter
- Trypanosoma brucei rhodesiense
- Benzodiazepines
- Cysteine Endopeptidases
- Cysteine Proteinase Inhibitors
- Antiprotozoal Agents
- Parasitic Sensitivity Tests
- Molecular Structure
- Structure-Activity Relationship
- Dose-Response Relationship, Drug
- Peptidomimetics
- Drug Development
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2020
- Paginierung
- 995 - 1001
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Datum der Datenerfassung
- 2020
- Titel
- Development of Novel Benzodiazepine-Based Peptidomimetics as Inhibitors of Rhodesain from Trypanosoma brucei rhodesiense.
- Sub types
- Research Support, Non-U.S. Gov't
- Journal Article
- Ausgabe der Zeitschrift
- 15
Datenquelle: Europe PubMed Central
- Abstract
- Starting from the reversible rhodesain inhibitors 1 a-c, which have Ki values towards the target protease in the low-micromolar range, we have designed a series of peptidomimetics, 2 a-g, that contain a benzodiazepine scaffold as a β-turn mimetic; they are characterized by a specific peptide sequence for the inhibition of rhodesain. Considering that irreversible inhibition is strongly desirable in the case of a parasitic target, a vinyl ester moiety acting as Michael-acceptor was introduced as the warhead; this portion was functionalized in order to evaluate the size of corresponding enzyme pocket that could accommodate this substituent. With this investigation, we identified an irreversible rhodesain inhibitor (i. e., 2 g) with a k2nd value of 90 000 M-1 min-1 that showed antitrypanosomal activity in the low-micromolar range (EC50 =1.25 μM), this may be considered a promising lead compound in the drug-discovery process for treating human African trypanosomiasis (HAT).
- Autoren
- Carla Di Chio
- Santo Previti
- Giorgio Amendola
- Sandro Cosconati
- Tanja Schirmeister
- Maria Zappalà
- Roberta Ettari
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/32329206
- DOI
- 10.1002/cmdc.202000158
- eISSN
- 1860-7187
- Ausgabe der Veröffentlichung
- 11
- Zeitschrift
- ChemMedChem
- Schlüsselwörter
- Michael acceptors
- Trypanosoma brucei
- benzodiazepine scaffold
- human African trypanosomiasis
- peptidomimetics
- rhodesain
- Antiprotozoal Agents
- Benzodiazepines
- Cysteine Endopeptidases
- Cysteine Proteinase Inhibitors
- Dose-Response Relationship, Drug
- Drug Development
- Molecular Structure
- Parasitic Sensitivity Tests
- Peptidomimetics
- Structure-Activity Relationship
- Trypanosoma brucei rhodesiense
- Sprache
- eng
- Country
- Germany
- Paginierung
- 995 - 1001
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2021
- Titel
- Development of Novel Benzodiazepine-Based Peptidomimetics as Inhibitors of Rhodesain from Trypanosoma brucei rhodesiense.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 15
Datenquelle: PubMed
- Autoren
- Carla Di Chio
- Santo Previti
- Giorgio Amendola
- Sandro Cosconati
- Tanja Schirmeister
- Maria Zappalà
- Roberta Ettari
- Zeitschrift
- ChemMedChem
- Artikelnummer
- 11
- Paginierung
- 995 - 1001
- Datum der Veröffentlichung
- 2020
- Herausgeber
- Wiley Online Library
- Datum der Datenerfassung
- 2021
- Titel
- Development of Novel Benzodiazepine-Based Peptidomimetics as Inhibitors of Rhodesain from Trypanosoma brucei rhodesiense
- Sub types
- article
- Ausgabe der Zeitschrift
- 15
Datenquelle: Manual
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