Investigation of an Allosteric Deoxyhypusine Synthase Inhibitor in <i<P. falciparum</i<

The treatment of a variety of protozoal infections, in particular those causing disabling human diseases, is still hampered by a lack of drugs or increasing resistance to registered drugs. However, in recent years, remarkable progress has been achieved to combat neglected tropical diseases by sequencing the parasites’ genomes or the validation of new targets in the parasites by novel genetic manipulation techniques, leading to loss of function. The novel amino acid hypusine is a posttranslational modification (PTM) that occurs in eukaryotic initiation factor 5A (EIF5A) at a specific lysine residue. This modification occurs by two steps catalyzed by deoxyhypusine synthase (<i<dhs</i<) and deoxyhypusine hydroxylase (DOHH) enzymes. <i<dhs</i< from <i<Plasmodium</i< has been validated as a druggable target by small molecules and reverse genetics. Recently, the synthesis of a series of human <i<dhs</i< inhibitors led to 6-bromo-<i<N</i<-(1<i<H</i<-indol-4yl)-1-benzothiophene-2-carboxamide, a potent allosteric inhibitor with an IC<sub<50</sub< value of 0.062 µM. We investigated this allosteric <i<dhs</i< inhibitor in <i<Plasmodium</i<. In vitro <i<P. falciparum</i< growth assays showed weak inhibition activity, with IC<sub<50</sub< values of 46.1 µM for the Dd2 strain and 51.5 µM for the 3D7 strain, respectively. The antimalarial activity could not be attributed to the targeting of the <i<Pfdhs</i< gene, as shown by chemogenomic profiling with transgenically modified <i<P. falciparum</i< lines. Moreover, in dose-dependent enzymatic assays with purified recombinant <i<P. falciparum</i< <i<dhs</i< protein, only 45% inhibition was observed at an inhibitor dose of 0.4 µM. These data are in agreement with a homology-modeled <i<Pfdhs</i<, suggesting significant structural differences in the allosteric site between the human and parasite enzymes. Virtual screening of the allosteric database identified candidate ligand binding to novel binding pockets identified in <i<P. falciparum</i< <i<dhs</i<, which might foster the development of parasite-specific inhibitors. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Aiyada Aroonsri [verfasserIn] Chayaphat Wongsombat [verfasserIn] Philip Shaw [verfasserIn] Siegrid Franke [verfasserIn] Jude Przyborski [verfasserIn] Annette Kaiser [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	chemogenomic profiling hypusine bromobenzothiophene deoxyhypusine synthase allosteric inhibitor

Übergeordnetes Werk:	In: Molecules - MDPI AG, 2003, 27(2022), 8, p 2463
Übergeordnetes Werk:	volume:27 ; year:2022 ; number:8, p 2463

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/molecules27082463

Katalog-ID:	DOAJ034043519

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allfields	10.3390/molecules27082463 doi (DE-627)DOAJ034043519 (DE-599)DOAJb685e9ff2eb24e8abb8d2b34f42cb778 DE-627 ger DE-627 rakwb eng QD241-441 Aiyada Aroonsri verfasserin aut Investigation of an Allosteric Deoxyhypusine Synthase Inhibitor in <i<P. falciparum</i< 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The treatment of a variety of protozoal infections, in particular those causing disabling human diseases, is still hampered by a lack of drugs or increasing resistance to registered drugs. However, in recent years, remarkable progress has been achieved to combat neglected tropical diseases by sequencing the parasites’ genomes or the validation of new targets in the parasites by novel genetic manipulation techniques, leading to loss of function. The novel amino acid hypusine is a posttranslational modification (PTM) that occurs in eukaryotic initiation factor 5A (EIF5A) at a specific lysine residue. This modification occurs by two steps catalyzed by deoxyhypusine synthase (<i<dhs</i<) and deoxyhypusine hydroxylase (DOHH) enzymes. <i<dhs</i< from <i<Plasmodium</i< has been validated as a druggable target by small molecules and reverse genetics. Recently, the synthesis of a series of human <i<dhs</i< inhibitors led to 6-bromo-<i<N</i<-(1<i<H</i<-indol-4yl)-1-benzothiophene-2-carboxamide, a potent allosteric inhibitor with an IC<sub<50</sub< value of 0.062 µM. We investigated this allosteric <i<dhs</i< inhibitor in <i<Plasmodium</i<. In vitro <i<P. falciparum</i< growth assays showed weak inhibition activity, with IC<sub<50</sub< values of 46.1 µM for the Dd2 strain and 51.5 µM for the 3D7 strain, respectively. The antimalarial activity could not be attributed to the targeting of the <i<Pfdhs</i< gene, as shown by chemogenomic profiling with transgenically modified <i<P. falciparum</i< lines. Moreover, in dose-dependent enzymatic assays with purified recombinant <i<P. falciparum</i< <i<dhs</i< protein, only 45% inhibition was observed at an inhibitor dose of 0.4 µM. These data are in agreement with a homology-modeled <i<Pfdhs</i<, suggesting significant structural differences in the allosteric site between the human and parasite enzymes. Virtual screening of the allosteric database identified candidate ligand binding to novel binding pockets identified in <i<P. falciparum</i< <i<dhs</i<, which might foster the development of parasite-specific inhibitors. chemogenomic profiling hypusine bromobenzothiophene deoxyhypusine synthase <i<glmS</i< riboswitch allosteric inhibitor Organic chemistry Chayaphat Wongsombat verfasserin aut Philip Shaw verfasserin aut Siegrid Franke verfasserin aut Jude Przyborski verfasserin aut Annette Kaiser verfasserin aut In Molecules MDPI AG, 2003 27(2022), 8, p 2463 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:27 year:2022 number:8, p 2463 https://doi.org/10.3390/molecules27082463 kostenfrei https://doaj.org/article/b685e9ff2eb24e8abb8d2b34f42cb778 kostenfrei https://www.mdpi.com/1420-3049/27/8/2463 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 27 2022 8, p 2463
spelling	10.3390/molecules27082463 doi (DE-627)DOAJ034043519 (DE-599)DOAJb685e9ff2eb24e8abb8d2b34f42cb778 DE-627 ger DE-627 rakwb eng QD241-441 Aiyada Aroonsri verfasserin aut Investigation of an Allosteric Deoxyhypusine Synthase Inhibitor in <i<P. falciparum</i< 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The treatment of a variety of protozoal infections, in particular those causing disabling human diseases, is still hampered by a lack of drugs or increasing resistance to registered drugs. However, in recent years, remarkable progress has been achieved to combat neglected tropical diseases by sequencing the parasites’ genomes or the validation of new targets in the parasites by novel genetic manipulation techniques, leading to loss of function. The novel amino acid hypusine is a posttranslational modification (PTM) that occurs in eukaryotic initiation factor 5A (EIF5A) at a specific lysine residue. This modification occurs by two steps catalyzed by deoxyhypusine synthase (<i<dhs</i<) and deoxyhypusine hydroxylase (DOHH) enzymes. <i<dhs</i< from <i<Plasmodium</i< has been validated as a druggable target by small molecules and reverse genetics. Recently, the synthesis of a series of human <i<dhs</i< inhibitors led to 6-bromo-<i<N</i<-(1<i<H</i<-indol-4yl)-1-benzothiophene-2-carboxamide, a potent allosteric inhibitor with an IC<sub<50</sub< value of 0.062 µM. We investigated this allosteric <i<dhs</i< inhibitor in <i<Plasmodium</i<. In vitro <i<P. falciparum</i< growth assays showed weak inhibition activity, with IC<sub<50</sub< values of 46.1 µM for the Dd2 strain and 51.5 µM for the 3D7 strain, respectively. The antimalarial activity could not be attributed to the targeting of the <i<Pfdhs</i< gene, as shown by chemogenomic profiling with transgenically modified <i<P. falciparum</i< lines. Moreover, in dose-dependent enzymatic assays with purified recombinant <i<P. falciparum</i< <i<dhs</i< protein, only 45% inhibition was observed at an inhibitor dose of 0.4 µM. These data are in agreement with a homology-modeled <i<Pfdhs</i<, suggesting significant structural differences in the allosteric site between the human and parasite enzymes. Virtual screening of the allosteric database identified candidate ligand binding to novel binding pockets identified in <i<P. falciparum</i< <i<dhs</i<, which might foster the development of parasite-specific inhibitors. chemogenomic profiling hypusine bromobenzothiophene deoxyhypusine synthase <i<glmS</i< riboswitch allosteric inhibitor Organic chemistry Chayaphat Wongsombat verfasserin aut Philip Shaw verfasserin aut Siegrid Franke verfasserin aut Jude Przyborski verfasserin aut Annette Kaiser verfasserin aut In Molecules MDPI AG, 2003 27(2022), 8, p 2463 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:27 year:2022 number:8, p 2463 https://doi.org/10.3390/molecules27082463 kostenfrei https://doaj.org/article/b685e9ff2eb24e8abb8d2b34f42cb778 kostenfrei https://www.mdpi.com/1420-3049/27/8/2463 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 27 2022 8, p 2463
allfields_unstemmed	10.3390/molecules27082463 doi (DE-627)DOAJ034043519 (DE-599)DOAJb685e9ff2eb24e8abb8d2b34f42cb778 DE-627 ger DE-627 rakwb eng QD241-441 Aiyada Aroonsri verfasserin aut Investigation of an Allosteric Deoxyhypusine Synthase Inhibitor in <i<P. falciparum</i< 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The treatment of a variety of protozoal infections, in particular those causing disabling human diseases, is still hampered by a lack of drugs or increasing resistance to registered drugs. However, in recent years, remarkable progress has been achieved to combat neglected tropical diseases by sequencing the parasites’ genomes or the validation of new targets in the parasites by novel genetic manipulation techniques, leading to loss of function. The novel amino acid hypusine is a posttranslational modification (PTM) that occurs in eukaryotic initiation factor 5A (EIF5A) at a specific lysine residue. This modification occurs by two steps catalyzed by deoxyhypusine synthase (<i<dhs</i<) and deoxyhypusine hydroxylase (DOHH) enzymes. <i<dhs</i< from <i<Plasmodium</i< has been validated as a druggable target by small molecules and reverse genetics. Recently, the synthesis of a series of human <i<dhs</i< inhibitors led to 6-bromo-<i<N</i<-(1<i<H</i<-indol-4yl)-1-benzothiophene-2-carboxamide, a potent allosteric inhibitor with an IC<sub<50</sub< value of 0.062 µM. We investigated this allosteric <i<dhs</i< inhibitor in <i<Plasmodium</i<. In vitro <i<P. falciparum</i< growth assays showed weak inhibition activity, with IC<sub<50</sub< values of 46.1 µM for the Dd2 strain and 51.5 µM for the 3D7 strain, respectively. The antimalarial activity could not be attributed to the targeting of the <i<Pfdhs</i< gene, as shown by chemogenomic profiling with transgenically modified <i<P. falciparum</i< lines. Moreover, in dose-dependent enzymatic assays with purified recombinant <i<P. falciparum</i< <i<dhs</i< protein, only 45% inhibition was observed at an inhibitor dose of 0.4 µM. These data are in agreement with a homology-modeled <i<Pfdhs</i<, suggesting significant structural differences in the allosteric site between the human and parasite enzymes. Virtual screening of the allosteric database identified candidate ligand binding to novel binding pockets identified in <i<P. falciparum</i< <i<dhs</i<, which might foster the development of parasite-specific inhibitors. chemogenomic profiling hypusine bromobenzothiophene deoxyhypusine synthase <i<glmS</i< riboswitch allosteric inhibitor Organic chemistry Chayaphat Wongsombat verfasserin aut Philip Shaw verfasserin aut Siegrid Franke verfasserin aut Jude Przyborski verfasserin aut Annette Kaiser verfasserin aut In Molecules MDPI AG, 2003 27(2022), 8, p 2463 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:27 year:2022 number:8, p 2463 https://doi.org/10.3390/molecules27082463 kostenfrei https://doaj.org/article/b685e9ff2eb24e8abb8d2b34f42cb778 kostenfrei https://www.mdpi.com/1420-3049/27/8/2463 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 27 2022 8, p 2463
allfieldsGer	10.3390/molecules27082463 doi (DE-627)DOAJ034043519 (DE-599)DOAJb685e9ff2eb24e8abb8d2b34f42cb778 DE-627 ger DE-627 rakwb eng QD241-441 Aiyada Aroonsri verfasserin aut Investigation of an Allosteric Deoxyhypusine Synthase Inhibitor in <i<P. falciparum</i< 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The treatment of a variety of protozoal infections, in particular those causing disabling human diseases, is still hampered by a lack of drugs or increasing resistance to registered drugs. However, in recent years, remarkable progress has been achieved to combat neglected tropical diseases by sequencing the parasites’ genomes or the validation of new targets in the parasites by novel genetic manipulation techniques, leading to loss of function. The novel amino acid hypusine is a posttranslational modification (PTM) that occurs in eukaryotic initiation factor 5A (EIF5A) at a specific lysine residue. This modification occurs by two steps catalyzed by deoxyhypusine synthase (<i<dhs</i<) and deoxyhypusine hydroxylase (DOHH) enzymes. <i<dhs</i< from <i<Plasmodium</i< has been validated as a druggable target by small molecules and reverse genetics. Recently, the synthesis of a series of human <i<dhs</i< inhibitors led to 6-bromo-<i<N</i<-(1<i<H</i<-indol-4yl)-1-benzothiophene-2-carboxamide, a potent allosteric inhibitor with an IC<sub<50</sub< value of 0.062 µM. We investigated this allosteric <i<dhs</i< inhibitor in <i<Plasmodium</i<. In vitro <i<P. falciparum</i< growth assays showed weak inhibition activity, with IC<sub<50</sub< values of 46.1 µM for the Dd2 strain and 51.5 µM for the 3D7 strain, respectively. The antimalarial activity could not be attributed to the targeting of the <i<Pfdhs</i< gene, as shown by chemogenomic profiling with transgenically modified <i<P. falciparum</i< lines. Moreover, in dose-dependent enzymatic assays with purified recombinant <i<P. falciparum</i< <i<dhs</i< protein, only 45% inhibition was observed at an inhibitor dose of 0.4 µM. These data are in agreement with a homology-modeled <i<Pfdhs</i<, suggesting significant structural differences in the allosteric site between the human and parasite enzymes. Virtual screening of the allosteric database identified candidate ligand binding to novel binding pockets identified in <i<P. falciparum</i< <i<dhs</i<, which might foster the development of parasite-specific inhibitors. chemogenomic profiling hypusine bromobenzothiophene deoxyhypusine synthase <i<glmS</i< riboswitch allosteric inhibitor Organic chemistry Chayaphat Wongsombat verfasserin aut Philip Shaw verfasserin aut Siegrid Franke verfasserin aut Jude Przyborski verfasserin aut Annette Kaiser verfasserin aut In Molecules MDPI AG, 2003 27(2022), 8, p 2463 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:27 year:2022 number:8, p 2463 https://doi.org/10.3390/molecules27082463 kostenfrei https://doaj.org/article/b685e9ff2eb24e8abb8d2b34f42cb778 kostenfrei https://www.mdpi.com/1420-3049/27/8/2463 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 27 2022 8, p 2463
allfieldsSound	10.3390/molecules27082463 doi (DE-627)DOAJ034043519 (DE-599)DOAJb685e9ff2eb24e8abb8d2b34f42cb778 DE-627 ger DE-627 rakwb eng QD241-441 Aiyada Aroonsri verfasserin aut Investigation of an Allosteric Deoxyhypusine Synthase Inhibitor in <i<P. falciparum</i< 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The treatment of a variety of protozoal infections, in particular those causing disabling human diseases, is still hampered by a lack of drugs or increasing resistance to registered drugs. However, in recent years, remarkable progress has been achieved to combat neglected tropical diseases by sequencing the parasites’ genomes or the validation of new targets in the parasites by novel genetic manipulation techniques, leading to loss of function. The novel amino acid hypusine is a posttranslational modification (PTM) that occurs in eukaryotic initiation factor 5A (EIF5A) at a specific lysine residue. This modification occurs by two steps catalyzed by deoxyhypusine synthase (<i<dhs</i<) and deoxyhypusine hydroxylase (DOHH) enzymes. <i<dhs</i< from <i<Plasmodium</i< has been validated as a druggable target by small molecules and reverse genetics. Recently, the synthesis of a series of human <i<dhs</i< inhibitors led to 6-bromo-<i<N</i<-(1<i<H</i<-indol-4yl)-1-benzothiophene-2-carboxamide, a potent allosteric inhibitor with an IC<sub<50</sub< value of 0.062 µM. We investigated this allosteric <i<dhs</i< inhibitor in <i<Plasmodium</i<. In vitro <i<P. falciparum</i< growth assays showed weak inhibition activity, with IC<sub<50</sub< values of 46.1 µM for the Dd2 strain and 51.5 µM for the 3D7 strain, respectively. The antimalarial activity could not be attributed to the targeting of the <i<Pfdhs</i< gene, as shown by chemogenomic profiling with transgenically modified <i<P. falciparum</i< lines. Moreover, in dose-dependent enzymatic assays with purified recombinant <i<P. falciparum</i< <i<dhs</i< protein, only 45% inhibition was observed at an inhibitor dose of 0.4 µM. These data are in agreement with a homology-modeled <i<Pfdhs</i<, suggesting significant structural differences in the allosteric site between the human and parasite enzymes. Virtual screening of the allosteric database identified candidate ligand binding to novel binding pockets identified in <i<P. falciparum</i< <i<dhs</i<, which might foster the development of parasite-specific inhibitors. chemogenomic profiling hypusine bromobenzothiophene deoxyhypusine synthase <i<glmS</i< riboswitch allosteric inhibitor Organic chemistry Chayaphat Wongsombat verfasserin aut Philip Shaw verfasserin aut Siegrid Franke verfasserin aut Jude Przyborski verfasserin aut Annette Kaiser verfasserin aut In Molecules MDPI AG, 2003 27(2022), 8, p 2463 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:27 year:2022 number:8, p 2463 https://doi.org/10.3390/molecules27082463 kostenfrei https://doaj.org/article/b685e9ff2eb24e8abb8d2b34f42cb778 kostenfrei https://www.mdpi.com/1420-3049/27/8/2463 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 27 2022 8, p 2463
language	English
source	In Molecules 27(2022), 8, p 2463 volume:27 year:2022 number:8, p 2463
sourceStr	In Molecules 27(2022), 8, p 2463 volume:27 year:2022 number:8, p 2463
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	chemogenomic profiling hypusine bromobenzothiophene deoxyhypusine synthase <i<glmS</i< riboswitch allosteric inhibitor Organic chemistry
isfreeaccess_bool	true
container_title	Molecules
authorswithroles_txt_mv	Aiyada Aroonsri @@aut@@ Chayaphat Wongsombat @@aut@@ Philip Shaw @@aut@@ Siegrid Franke @@aut@@ Jude Przyborski @@aut@@ Annette Kaiser @@aut@@
publishDateDaySort_date	2022-01-01T00:00:00Z
hierarchy_top_id	311313132
id	DOAJ034043519
language_de	englisch
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callnumber-first	Q - Science
author	Aiyada Aroonsri
spellingShingle	Aiyada Aroonsri misc QD241-441 misc chemogenomic profiling misc hypusine misc bromobenzothiophene misc deoxyhypusine synthase misc <i<glmS</i< riboswitch misc allosteric inhibitor misc Organic chemistry Investigation of an Allosteric Deoxyhypusine Synthase Inhibitor in <i<P. falciparum</i<
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topic_title	QD241-441 Investigation of an Allosteric Deoxyhypusine Synthase Inhibitor in <i<P. falciparum</i< chemogenomic profiling hypusine bromobenzothiophene deoxyhypusine synthase <i<glmS</i< riboswitch allosteric inhibitor
topic	misc QD241-441 misc chemogenomic profiling misc hypusine misc bromobenzothiophene misc deoxyhypusine synthase misc <i<glmS</i< riboswitch misc allosteric inhibitor misc Organic chemistry
topic_unstemmed	misc QD241-441 misc chemogenomic profiling misc hypusine misc bromobenzothiophene misc deoxyhypusine synthase misc <i<glmS</i< riboswitch misc allosteric inhibitor misc Organic chemistry
topic_browse	misc QD241-441 misc chemogenomic profiling misc hypusine misc bromobenzothiophene misc deoxyhypusine synthase misc <i<glmS</i< riboswitch misc allosteric inhibitor misc Organic chemistry
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title	Investigation of an Allosteric Deoxyhypusine Synthase Inhibitor in <i<P. falciparum</i<
ctrlnum	(DE-627)DOAJ034043519 (DE-599)DOAJb685e9ff2eb24e8abb8d2b34f42cb778
title_full	Investigation of an Allosteric Deoxyhypusine Synthase Inhibitor in <i<P. falciparum</i<
author_sort	Aiyada Aroonsri
journal	Molecules
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author_browse	Aiyada Aroonsri Chayaphat Wongsombat Philip Shaw Siegrid Franke Jude Przyborski Annette Kaiser
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class	QD241-441
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author-letter	Aiyada Aroonsri
doi_str_mv	10.3390/molecules27082463
author2-role	verfasserin
title_sort	investigation of an allosteric deoxyhypusine synthase inhibitor in <i<p. falciparum</i<
callnumber	QD241-441
title_auth	Investigation of an Allosteric Deoxyhypusine Synthase Inhibitor in <i<P. falciparum</i<
abstract	The treatment of a variety of protozoal infections, in particular those causing disabling human diseases, is still hampered by a lack of drugs or increasing resistance to registered drugs. However, in recent years, remarkable progress has been achieved to combat neglected tropical diseases by sequencing the parasites’ genomes or the validation of new targets in the parasites by novel genetic manipulation techniques, leading to loss of function. The novel amino acid hypusine is a posttranslational modification (PTM) that occurs in eukaryotic initiation factor 5A (EIF5A) at a specific lysine residue. This modification occurs by two steps catalyzed by deoxyhypusine synthase (<i<dhs</i<) and deoxyhypusine hydroxylase (DOHH) enzymes. <i<dhs</i< from <i<Plasmodium</i< has been validated as a druggable target by small molecules and reverse genetics. Recently, the synthesis of a series of human <i<dhs</i< inhibitors led to 6-bromo-<i<N</i<-(1<i<H</i<-indol-4yl)-1-benzothiophene-2-carboxamide, a potent allosteric inhibitor with an IC<sub<50</sub< value of 0.062 µM. We investigated this allosteric <i<dhs</i< inhibitor in <i<Plasmodium</i<. In vitro <i<P. falciparum</i< growth assays showed weak inhibition activity, with IC<sub<50</sub< values of 46.1 µM for the Dd2 strain and 51.5 µM for the 3D7 strain, respectively. The antimalarial activity could not be attributed to the targeting of the <i<Pfdhs</i< gene, as shown by chemogenomic profiling with transgenically modified <i<P. falciparum</i< lines. Moreover, in dose-dependent enzymatic assays with purified recombinant <i<P. falciparum</i< <i<dhs</i< protein, only 45% inhibition was observed at an inhibitor dose of 0.4 µM. These data are in agreement with a homology-modeled <i<Pfdhs</i<, suggesting significant structural differences in the allosteric site between the human and parasite enzymes. Virtual screening of the allosteric database identified candidate ligand binding to novel binding pockets identified in <i<P. falciparum</i< <i<dhs</i<, which might foster the development of parasite-specific inhibitors.
abstractGer	The treatment of a variety of protozoal infections, in particular those causing disabling human diseases, is still hampered by a lack of drugs or increasing resistance to registered drugs. However, in recent years, remarkable progress has been achieved to combat neglected tropical diseases by sequencing the parasites’ genomes or the validation of new targets in the parasites by novel genetic manipulation techniques, leading to loss of function. The novel amino acid hypusine is a posttranslational modification (PTM) that occurs in eukaryotic initiation factor 5A (EIF5A) at a specific lysine residue. This modification occurs by two steps catalyzed by deoxyhypusine synthase (<i<dhs</i<) and deoxyhypusine hydroxylase (DOHH) enzymes. <i<dhs</i< from <i<Plasmodium</i< has been validated as a druggable target by small molecules and reverse genetics. Recently, the synthesis of a series of human <i<dhs</i< inhibitors led to 6-bromo-<i<N</i<-(1<i<H</i<-indol-4yl)-1-benzothiophene-2-carboxamide, a potent allosteric inhibitor with an IC<sub<50</sub< value of 0.062 µM. We investigated this allosteric <i<dhs</i< inhibitor in <i<Plasmodium</i<. In vitro <i<P. falciparum</i< growth assays showed weak inhibition activity, with IC<sub<50</sub< values of 46.1 µM for the Dd2 strain and 51.5 µM for the 3D7 strain, respectively. The antimalarial activity could not be attributed to the targeting of the <i<Pfdhs</i< gene, as shown by chemogenomic profiling with transgenically modified <i<P. falciparum</i< lines. Moreover, in dose-dependent enzymatic assays with purified recombinant <i<P. falciparum</i< <i<dhs</i< protein, only 45% inhibition was observed at an inhibitor dose of 0.4 µM. These data are in agreement with a homology-modeled <i<Pfdhs</i<, suggesting significant structural differences in the allosteric site between the human and parasite enzymes. Virtual screening of the allosteric database identified candidate ligand binding to novel binding pockets identified in <i<P. falciparum</i< <i<dhs</i<, which might foster the development of parasite-specific inhibitors.
abstract_unstemmed	The treatment of a variety of protozoal infections, in particular those causing disabling human diseases, is still hampered by a lack of drugs or increasing resistance to registered drugs. However, in recent years, remarkable progress has been achieved to combat neglected tropical diseases by sequencing the parasites’ genomes or the validation of new targets in the parasites by novel genetic manipulation techniques, leading to loss of function. The novel amino acid hypusine is a posttranslational modification (PTM) that occurs in eukaryotic initiation factor 5A (EIF5A) at a specific lysine residue. This modification occurs by two steps catalyzed by deoxyhypusine synthase (<i<dhs</i<) and deoxyhypusine hydroxylase (DOHH) enzymes. <i<dhs</i< from <i<Plasmodium</i< has been validated as a druggable target by small molecules and reverse genetics. Recently, the synthesis of a series of human <i<dhs</i< inhibitors led to 6-bromo-<i<N</i<-(1<i<H</i<-indol-4yl)-1-benzothiophene-2-carboxamide, a potent allosteric inhibitor with an IC<sub<50</sub< value of 0.062 µM. We investigated this allosteric <i<dhs</i< inhibitor in <i<Plasmodium</i<. In vitro <i<P. falciparum</i< growth assays showed weak inhibition activity, with IC<sub<50</sub< values of 46.1 µM for the Dd2 strain and 51.5 µM for the 3D7 strain, respectively. The antimalarial activity could not be attributed to the targeting of the <i<Pfdhs</i< gene, as shown by chemogenomic profiling with transgenically modified <i<P. falciparum</i< lines. Moreover, in dose-dependent enzymatic assays with purified recombinant <i<P. falciparum</i< <i<dhs</i< protein, only 45% inhibition was observed at an inhibitor dose of 0.4 µM. These data are in agreement with a homology-modeled <i<Pfdhs</i<, suggesting significant structural differences in the allosteric site between the human and parasite enzymes. Virtual screening of the allosteric database identified candidate ligand binding to novel binding pockets identified in <i<P. falciparum</i< <i<dhs</i<, which might foster the development of parasite-specific inhibitors.
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container_issue	8, p 2463
title_short	Investigation of an Allosteric Deoxyhypusine Synthase Inhibitor in <i<P. falciparum</i<
url	https://doi.org/10.3390/molecules27082463 https://doaj.org/article/b685e9ff2eb24e8abb8d2b34f42cb778 https://www.mdpi.com/1420-3049/27/8/2463 https://doaj.org/toc/1420-3049
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Investigation of an Allosteric Deoxyhypusine Synthase Inhibitor in <i<P. falciparum</i<

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