In Silico screening on the three-dimensional model of the Plasmodium vivax SUB1 protease leads to the validation of a novel anti-parasite compound.

Anthony Bouillon 1 David Giganti 2 Christophe Benedet 3 Olivier Gorgette 1 Stéphane Pêtres 4 Elodie Crublet 4 Christine Girard-Blanc 4 Benoit Witkowski 3 Didier Ménard 3 Michael Nilges 2 Odile Mercereau-Puijalon 1 Véronique Stoven 5, 6 Jean-Christophe Barale 1, *
* Auteur correspondant
1 Immunologie moléculaire des parasites
2 Bioinformatique structurale
3 Institut Pasteur du Cambodge
4 Production de Protéines Recombinantes et d'Anticorps (Plate-Forme)
5 Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
6 CBIO - Centre de Bioinformatique
Abstract : Widespread drug resistance calls for the urgent development of new antimalarials that target novel steps in the life cycle of Plasmodium falciparum and Plasmodium vivax. The essential subtilisin-like serine protease SUB1 of Plasmodium merozoites plays a dual role in egress from and invasion into host erythrocytes. It belongs to a new generation of attractive drug targets against which specific potent inhibitors are actively searched. We characterize here the P. vivax SUB1 enzyme and show that it displays a typical auto-processing pattern and apical localization in P. vivax merozoites. To search for small PvSUB1 inhibitors, we took advantage of the similarity of SUB1 with bacterial subtilisins and generated P. vivax SUB1 three-dimensional models. The structure-based virtual screening of a large commercial chemical compounds library identified 306 virtual best hits, of which 37 were experimentally confirmed inhibitors and 5 had Ki values of <50 μM for PvSUB1. Interestingly, they belong to different chemical families. The most promising competitive inhibitor of PvSUB1 (compound 2) was equally active on PfSUB1 and displayed anti-P. falciparum and Plasmodium berghei activity in vitro and in vivo, respectively. Compound 2 inhibited the endogenous PfSUB1 as illustrated by the inhibited maturation of its natural substrate PfSERA5 and inhibited parasite egress and subsequent erythrocyte invasion. These data indicate that the strategy of in silico screening of three-dimensional models to select for virtual inhibitors combined with stringent biological validation successfully identified several inhibitors of the PvSUB1 enzyme. The most promising hit proved to be a potent cross-inhibitor of PlasmodiumSUB1, laying the groundwork for the development of a globally active small compound antimalarial.
Keywords : Drug Target Egress Malaria Parasitology Plasmodium vivax Protease Protease Inhibitor Structural Biology Subtilisin Virtual Screening
Type de document :
Article dans une revue
Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2013, 288, pp.18561-73. 〈10.1074/jbc.M113.456764〉
Liste complète des métadonnées

Littérature citée [50 références]  Voir  Masquer  Télécharger
https://hal-pasteur.archives-ouvertes.fr/pasteur-01457905
Contributeur : Maya Um <>
Soumis le : lundi 6 février 2017 - 15:59:26
Dernière modification le : lundi 8 octobre 2018 - 17:44:04
Document(s) archivé(s) le : dimanche 7 mai 2017 - 14:36:05

Fichier

135 - Nilges.pdf
Fichiers éditeurs autorisés sur une archive ouverte

Identifiants

Collections

PASTEUR | ENSMP | RIIP_CAMBODGE | CURIE | FNCLCC | ENSMP_CBIO | PSL | RIIP | PARISTECH

Citation

Anthony Bouillon, David Giganti, Christophe Benedet, Olivier Gorgette, Stéphane Pêtres, et al.. In Silico screening on the three-dimensional model of the Plasmodium vivax SUB1 protease leads to the validation of a novel anti-parasite compound.. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2013, 288, pp.18561-73. 〈10.1074/jbc.M113.456764〉. 〈pasteur-01457905〉

Exporter

BibTeX TEI DC DCterms EndNote

Partager

Métriques

Consultations de la notice

159

Téléchargements de fichiers

138