Influence of amino acid size at the P3 position of N-Cbz-tripeptide Michael acceptors targeting falcipain-2 and rhodesain for the treatment of malaria and human african trypanosomiasis

Publikationstyp:
Zeitschriftenaufsatz
Metadaten:
Autoren
  • Santo Previti
  • Roberta Ettari
  • Carla Di Chio
  • Jenny Legac
  • Marta Bogacz
  • Collin Zimmer
  • Tanja Schirmeister
  • Philip J Rosenthal
  • Maria Zappala
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:001001349200001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.bioorg.2023.106587
eISSN
1090-2120
Externe Identifier
  • Clarivate Analytics Document Solution ID: I2TC7
  • PubMed Identifier: 37163812
ISSN
0045-2068
Zeitschrift
BIOORGANIC CHEMISTRY
Schlüsselwörter
  • Falcipain-2
  • Rhodesain
  • Protozoan cysteine proteases
  • Michael acceptors
  • Antimalarial
  • Antitrypanosomal
  • Neglected tropical diseases
Artikelnummer
ARTN 106587
Datum der Veröffentlichung
2023
Status
Published
Titel
Influence of amino acid size at the P3 position of N-Cbz-tripeptide Michael acceptors targeting falcipain-2 and rhodesain for the treatment of malaria and human african trypanosomiasis
Sub types
  • Article
Ausgabe der Zeitschrift
137

Datenquelle: Web of Science (Lite)

Andere Metadatenquellen:
Autoren
  • Santo Previti
  • Roberta Ettari
  • Carla Di Chio
  • Jenny Legac
  • Marta Bogacz
  • Collin Zimmer
  • Tanja Schirmeister
  • Philip J Rosenthal
  • Maria Zappalà
DOI
10.1016/j.bioorg.2023.106587
ISSN
0045-2068
Zeitschrift
Bioorganic Chemistry
Sprache
en
Artikelnummer
106587
Paginierung
106587 - 106587
Datum der Veröffentlichung
2023
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.bioorg.2023.106587
Datum der Datenerfassung
2024
Titel
Influence of amino acid size at the P3 position of N-Cbz-tripeptide Michael acceptors targeting falcipain-2 and rhodesain for the treatment of malaria and human african trypanosomiasis
Ausgabe der Zeitschrift
137

Datenquelle: Crossref

Abstract
In recent decades, several structure-activity relationship (SAR) studies provided potent inhibitors of the cysteine proteases falcipain-2 (FP-2) and rhodesain (RD) from Plasmodium falciparum and Trypanosoma brucei rhodesiense, respectively. Whilst the roles of the warhead and residues targeting the P1 and P2 pockets of the proteases were extensively investigated, the roles of the amino acids occupying the S3 pocket were not widely assessed. Herein we report the synthesis and biological evaluation of a set of novel Michael acceptors bearing amino acids of increasing size at the P3 site (1a-g/2a-g, SPR20-SPR33) against FP-2, RD, P. falciparum, and T. brucei. Overall, the Michael acceptors bearing small amino acids at the P3 site exhibited the most potent inhibitory properties towards FP-2. In contrast, analogues with bulky residues at the P3 position were very potent rhodesain inhibitors. In cell based assays, single-digit micromolar EC<sub>50</sub> values against the two protozoa were observed. These findings can be a starting point for the development of peptide-based FP-2 and RD inhibitors.
Addresses
  • Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale Stagno d'Alcontres 31, 98166 Messina, Italy. Electronic address: spreviti@unime.it.
Autoren
  • Santo Previti
  • Roberta Ettari
  • Carla Di Chio
  • Jenny Legac
  • Marta Bogacz
  • Collin Zimmer
  • Tanja Schirmeister
  • Philip J Rosenthal
  • Maria Zappalà
DOI
10.1016/j.bioorg.2023.106587
eISSN
1090-2120
Externe Identifier
  • PubMed Identifier: 37163812
Funding acknowledgements
  • German Research Foundation:
  • University of Messina:
Open access
false
ISSN
0045-2068
Zeitschrift
Bioorganic chemistry
Schlüsselwörter
  • Animals
  • Humans
  • Plasmodium falciparum
  • Malaria
  • Malaria, Falciparum
  • Trypanosomiasis, African
  • Amino Acids
  • Structure-Activity Relationship
Sprache
eng
Medium
Print-Electronic
Online publication date
2023
Paginierung
106587
Datum der Veröffentlichung
2023
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2023
Titel
Influence of amino acid size at the P3 position of N-Cbz-tripeptide Michael acceptors targeting falcipain-2 and rhodesain for the treatment of malaria and human african trypanosomiasis.
Sub types
  • Research Support, Non-U.S. Gov't
  • Journal Article
Ausgabe der Zeitschrift
137

Datenquelle: Europe PubMed Central

Abstract
In recent decades, several structure-activity relationship (SAR) studies provided potent inhibitors of the cysteine proteases falcipain-2 (FP-2) and rhodesain (RD) from Plasmodium falciparum and Trypanosoma brucei rhodesiense, respectively. Whilst the roles of the warhead and residues targeting the P1 and P2 pockets of the proteases were extensively investigated, the roles of the amino acids occupying the S3 pocket were not widely assessed. Herein we report the synthesis and biological evaluation of a set of novel Michael acceptors bearing amino acids of increasing size at the P3 site (1a-g/2a-g, SPR20-SPR33) against FP-2, RD, P. falciparum, and T. brucei. Overall, the Michael acceptors bearing small amino acids at the P3 site exhibited the most potent inhibitory properties towards FP-2. In contrast, analogues with bulky residues at the P3 position were very potent rhodesain inhibitors. In cell based assays, single-digit micromolar EC50 values against the two protozoa were observed. These findings can be a starting point for the development of peptide-based FP-2 and RD inhibitors.
Date of acceptance
2023
Autoren
  • Santo Previti
  • Roberta Ettari
  • Carla Di Chio
  • Jenny Legac
  • Marta Bogacz
  • Collin Zimmer
  • Tanja Schirmeister
  • Philip J Rosenthal
  • Maria Zappalà
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/37163812
DOI
10.1016/j.bioorg.2023.106587
eISSN
1090-2120
Zeitschrift
Bioorg Chem
Schlüsselwörter
  • Antimalarial
  • Antitrypanosomal
  • Falcipain-2
  • Michael acceptors
  • Neglected tropical diseases
  • Protozoan cysteine proteases
  • Rhodesain
  • Animals
  • Humans
  • Trypanosomiasis, African
  • Amino Acids
  • Malaria
  • Malaria, Falciparum
  • Plasmodium falciparum
  • Structure-Activity Relationship
Sprache
eng
Country
United States
Paginierung
106587
PII
S0045-2068(23)00248-1
Datum der Veröffentlichung
2023
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2023
Titel
Influence of amino acid size at the P3 position of N-Cbz-tripeptide Michael acceptors targeting falcipain-2 and rhodesain for the treatment of malaria and human african trypanosomiasis.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
137

Datenquelle: PubMed

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