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Structure–Activity Relationship Studies of Retro-1 Analogues against Shiga Toxin

Authors :
Lilia Ait Ouarab
Valérie Pons
David Montoir
Julien Barbier
Flora Ngadjeua
David-Alexandre Buisson
Jean-Christophe Cintrat
Alexandra Clerget
Daniel Gillet
Aurélien Michau
Lucie Caramelle
Hajer Abdelkafi
Service de Chimie Bio-Organique et de Marquage (SCBM)
Médicaments et Technologies pour la Santé (MTS)
Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA))
Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA))
Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS)
joint ministerial program of R&D against CBRNe risks
ANR-11-BSV2-0018,RETROscreen,Génétique chimique de la voie du transport rétrograde(2011)
Source :
Journal of Medicinal Chemistry, Journal of Medicinal Chemistry, American Chemical Society, 2020, 63 (15), pp.8114-8133. ⟨10.1021/acs.jmedchem.0c00298⟩, Journal of Medicinal Chemistry, 2020, 63 (15), pp.8114-8133. ⟨10.1021/acs.jmedchem.0c00298⟩
Publication Year :
2020
Publisher :
HAL CCSD, 2020.

Abstract

International audience; High-throughput screening has shown that Retro-1 inhibits ricin and Shiga toxins by diminishing their intracellular trafficking via the retrograde route, from early endosomes to the Golgi apparatus. To improve the activity of Retro-1, a structure-activity relationship (SAR) study was undertaken and yielded an analogue with a roughly 70-fold better half-maximal effective concentration (EC50) against Shiga toxin cytotoxicity measured in a cell protein synthesis assay.

Subjects

Subjects :
endocrine system
Endosome
Golgi Apparatus
Shiga Toxins
01 natural sciences
03 medical and health sciences
chemistry.chemical_compound
symbols.namesake
Structure-Activity Relationship
Drug Discovery
Structure–activity relationship
Humans
Cytotoxicity
030304 developmental biology
EC50
0303 health sciences
Benzodiazepinones
biology
Shiga toxin
Golgi apparatus
0104 chemical sciences
010404 medicinal & biomolecular chemistry
Protein Transport
Ricin
chemistry
Biochemistry
biology.protein
symbols
[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Molecular Medicine
Intracellular
HeLa Cells

Details

Language :
English
ISSN :
00222623 and 15204804
Database :
OpenAIRE
Journal :
Journal of Medicinal Chemistry, Journal of Medicinal Chemistry, American Chemical Society, 2020, 63 (15), pp.8114-8133. ⟨10.1021/acs.jmedchem.0c00298⟩, Journal of Medicinal Chemistry, 2020, 63 (15), pp.8114-8133. ⟨10.1021/acs.jmedchem.0c00298⟩
Accession number :
edsair.doi.dedup.....2e6531d88a6e098fcf3bb6654a4ec670
Full Text :
https://doi.org/10.1021/acs.jmedchem.0c00298⟩
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