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In Silico screening on the three-dimensional model of the Plasmodium vivax SUB1 protease leads to the validation of a novel anti-parasite compound.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2013 Jun 21; Vol. 288 (25), pp. 18561-73. Date of Electronic Publication: 2013 May 07. - Publication Year :
- 2013
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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.
- Subjects :
- Amino Acid Sequence
Animals
Antimalarials chemistry
Antimalarials pharmacology
Binding Sites genetics
Biocatalysis drug effects
Dose-Response Relationship, Drug
Erythrocytes drug effects
Erythrocytes parasitology
Female
Kinetics
Malaria parasitology
Malaria prevention & control
Merozoites drug effects
Merozoites enzymology
Mice
Models, Molecular
Molecular Sequence Data
Molecular Structure
Plasmodium berghei drug effects
Plasmodium berghei enzymology
Plasmodium vivax drug effects
Plasmodium vivax genetics
Protozoan Proteins genetics
Protozoan Proteins metabolism
Sequence Homology, Amino Acid
Serine Proteases genetics
Serine Proteases metabolism
Serine Proteinase Inhibitors chemistry
Serine Proteinase Inhibitors pharmacology
Sf9 Cells
Substrate Specificity
Plasmodium vivax enzymology
Protein Structure, Tertiary
Protozoan Proteins chemistry
Serine Proteases chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 288
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 23653352
- Full Text :
- https://doi.org/10.1074/jbc.M113.456764