In Silico Screening on the Three-dimensional Model of the Plasmodium vivax SUB1 Protease Leads to the Validation of a Novel Anti-parasite Compound

Bouillon, Anthony; Giganti, David; Benedet, Christophe; Gorgette, Olivier; Pêtres, Stéphane; Crublet, Elodie; Girard-Blanc, Christine; Witkowski, Benoît; Ménard, Didier; Nilges, Michaël; Mercereau‐Puijalon, Odile; Stoven, Véronique; Barale, Jean-Christophe

doi:10.1074/jbc.m113.456764

Cited by 23 publications

(64 citation statements)

References 54 publications

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“…138 140 150 160 170 180 190 200 210 220 230 240 250 260 270 ARTICLE segment is not an integral part of the mature catalytic domain: (i) the multiple alignment of Plasmodium SUB1 sequences (Fig. 1b) highlights the low complexity and high variability of this segment in different species; (ii) secondary maturation sites have been identified in this region for both P. vivax and P. falciparum 21,30 (Fig. 1b); and (iii) the PvSUB1 catalytic core (as seen in the crystal composed of residues 277-611) displays the same overall architecture as bacterial subtilisin catalytic domains (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1a). Inspection of the active site revealed that PvSUB1 had undergone autocleavage at its conserved primary maturation site 21 (Asp202, Fig. 1b), although the cleaved prodomain remains tightly associated to the catalytic core in the crystal.…”

Section: Resultsmentioning

confidence: 99%

“…1a). The purified enzyme was active on a set of fluorescence resonance energy transfer-based substrates corresponding to its cognate primary autoprocessing site or its parasite protein substrates 21,29 . The crystal structure of PvSUB1 was determined using molecular replacement methods and refined to 2.7 Å resolution (Table 1 and Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The PvSUB1 recombinant protein secreted in the supernatant of baculovirusinfected Sf9-insect cells was purified to homogeneity as previously described 21 ( Supplementary Fig. 1a).…”

Section: Resultsmentioning

confidence: 99%

“…Future anti-malarials needed to match the agenda of malaria eradication 18 should be equally efficient against both P. falciparum and P. vivax, and overcome resistance to existing drugs 19,20 by targeting yet untouched parasite biological functions of the hepatic and erythrocytic stages. Plasmodium SUB1 properties fulfill these criteria, as SUB1 is indeed highly conserved across Plasmodium species 9,21 , including P. falciparum and P. vivax, and SUB1 inhibitors have been shown to equally impair P. vivax and P. falciparum SUB1 enzymes 21 . In addition, SUB1 plays a dual essential role at both the hepatic and erythrocytic phases of the Plasmodium life cycle 12 .…”

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confidence: 99%

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A novel Plasmodium-specific prodomain fold regulates the malaria drug target SUB1 subtilase

et al. 2014

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The Plasmodium subtilase SUB1 plays a pivotal role during the egress of malaria parasites from host hepatocytes and erythrocytes. Here we report the crystal structure of full-length SUB1 from the human-infecting parasite Plasmodium vivax, revealing a bacterial-like catalytic domain in complex with a Plasmodium-specific prodomain. The latter displays a novel architecture with an amino-terminal insertion that functions as a 'belt', embracing the catalytic domain to further stabilize the quaternary structure of the pre-protease, and undergoes calcium-dependent autoprocessing during subsequent activation. Although dispensable for recombinant enzymatic activity, the SUB1 'belt' could not be deleted in Plasmodium berghei, suggesting an essential role of this domain for parasite development in vivo. The SUB1 structure not only provides a valuable platform to develop new anti-malarial candidates against this promising drug target, but also defines the Plasmodium-specific 'belt' domain as a key calcium-dependent regulator of SUB1 during parasite egress from host cells.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…The PvSUB1 recombinant protein secreted in the supernatant of baculovirusinfected Sf9-insect cells was purified to homogeneity as previously described 21 ( Supplementary Fig. 1a).…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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A novel Plasmodium-specific prodomain fold regulates the malaria drug target SUB1 subtilase

et al. 2014

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The proteolytic repertoire of malaria parasites

Sijwali

Rosenthal

2016

Advances in Malaria Research

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Quinoxaline-Based Inhibitors of Malarial Protease PfSUB1*

Kher

Penzo

Ebejer

et al. 2014

Chem Heterocycl Comp

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Bis(phenylamino)quinoxalines have been identified as a novel class of malarial protease PfSUB1 inhibitors by screening of Malaria Box compounds. The synthesis of analog series and investigation of their inhibitory activity provided preliminary structure-activity relationship to create in silico models for binding of these compounds into the active site of PfSUB1.The alarming spread of drug-resistant malaria has reinforced the search for drugs with a novel mode of action [1][2][3][4]. Inhibition of the malarial protease PfSUB1 (Plasmodium falciparum subtilisin-like serine protease-1) has been shown to be a promising approach to block the propagation of infection by preventing the maturation and egress of merozoites from the red blood cell [5][6][7][8]. Consequently, discovery of small molecule inhibitors for PfSUB1 has become an active field of investigation. However, only a limited number of compounds with activity in the sub-micromolar to micromolar range have been discovered so far [6-10]. Recently, we reported rationally designed peptidic ketoamides as sub-micromolar PfSUB1 inhibitors [11]. In parallel with these studies, we actively searched for non-peptidic inhibitors. For this purpose, we screened the Malaria Box, a collection of 400 compounds which have confirmed activity against the blood stage of Plasmodium falciparum [12]. Screening of this compound library using our previously-described PfSUB1 enzyme assay [11] revealed 2,3-bis(phenylamino)quinoxaline derivative 1a as a PfSUB1 inhibitor (IC 50 10 μM, see scheme and Table 1). Since also several structurally related 2-arylaminoquinoxalines show antimalarial activity in mice [13], as the next step we undertook the synthesis of quinoxaline 1a analogs in order to obtain preliminary structure-activity relationships.

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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

Cited by 23 publications

References 54 publications

A novel Plasmodium-specific prodomain fold regulates the malaria drug target SUB1 subtilase

A novel Plasmodium-specific prodomain fold regulates the malaria drug target SUB1 subtilase

The proteolytic repertoire of malaria parasites

Quinoxaline-Based Inhibitors of Malarial Protease PfSUB1*

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