Prevention of Alzheimer's disease-associated Abeta aggregation by rationally designed nonpeptidic beta-sheet ligands.
Identifieur interne : 003047 ( Main/Exploration ); précédent : 003046; suivant : 003048Prevention of Alzheimer's disease-associated Abeta aggregation by rationally designed nonpeptidic beta-sheet ligands.
Auteurs : Petra Rzepecki [États-Unis] ; Luitgard Nagel-Steger ; Sophie Feuerstein ; Uwe Linne ; Oliver Molt ; Reza Zadmard ; Katja Aschermann ; Markus Wehner ; Thomas Schrader ; Detlev RiesnerSource :
- The Journal of biological chemistry [ 0021-9258 ] ; 2004.
Descripteurs français
- KwdFr :
- Animaux, Centrifugation en gradient de densité, Fragments peptidiques (), Fragments peptidiques (génétique), Fragments peptidiques (métabolisme), Humains, Liaison hydrogène, Ligands, Maladie d'Alzheimer (anatomopathologie), Maladie d'Alzheimer (métabolisme), Modèles moléculaires, Peptides bêta-amyloïdes (), Peptides bêta-amyloïdes (génétique), Peptides bêta-amyloïdes (métabolisme), Pyrazoles (), Pyrazoles (métabolisme), Spectrométrie de fluorescence (), Structure moléculaire, Structure quaternaire des protéines, Structure secondaire des protéines.
- MESH :
- anatomopathologie : Maladie d'Alzheimer.
- génétique : Fragments peptidiques, Peptides bêta-amyloïdes.
- métabolisme : Fragments peptidiques, Maladie d'Alzheimer, Peptides bêta-amyloïdes, Pyrazoles.
- Animaux, Centrifugation en gradient de densité, Fragments peptidiques, Humains, Liaison hydrogène, Ligands, Modèles moléculaires, Peptides bêta-amyloïdes, Pyrazoles, Spectrométrie de fluorescence, Structure moléculaire, Structure quaternaire des protéines, Structure secondaire des protéines.
English descriptors
- KwdEn :
- Alzheimer Disease (metabolism), Alzheimer Disease (pathology), Amyloid beta-Peptides (chemistry), Amyloid beta-Peptides (genetics), Amyloid beta-Peptides (metabolism), Animals, Centrifugation, Density Gradient, Humans, Hydrogen Bonding, Ligands, Models, Molecular, Molecular Structure, Peptide Fragments (chemistry), Peptide Fragments (genetics), Peptide Fragments (metabolism), Protein Structure, Quaternary, Protein Structure, Secondary, Pyrazoles (chemistry), Pyrazoles (metabolism), Spectrometry, Fluorescence (methods).
- MESH :
- chemical , chemistry : Amyloid beta-Peptides, Peptide Fragments, Pyrazoles.
- chemical , genetics : Amyloid beta-Peptides, Peptide Fragments.
- metabolism : Alzheimer Disease, Amyloid beta-Peptides, Peptide Fragments, Pyrazoles.
- methods : Spectrometry, Fluorescence.
- pathology : Alzheimer Disease.
- Animals, Centrifugation, Density Gradient, Humans, Hydrogen Bonding, Ligands, Models, Molecular, Molecular Structure, Protein Structure, Quaternary, Protein Structure, Secondary.
Abstract
A new concept is introduced for the rational design of beta-sheet ligands, which prevent protein aggregation. Oligomeric acylated aminopyrazoles with a donor-acceptor-donor (DAD) hydrogen bond pattern complementary to that of a beta-sheet efficiently block the solvent-exposed beta-sheet portions in Abeta-(1-40) and thereby prevent formation of insoluble protein aggregates. Density gradient centrifugation revealed that in the initial phase, the size of Abeta aggregates was efficiently kept between the trimeric and 15-meric state, whereas after 5 days an additional high molecular weight fraction appeared. With fluorescence correlation spectroscopy (FCS) exactly those two, i.e. a dimeric aminopyrazole with an oxalyl spacer and a trimeric head-to-tail connected aminopyrazole, of nine similar aminopyrazole ligands were identified as efficient aggregation retardants whose minimum energy conformations showed a perfect complementarity to a beta-sheet. The concentration dependence of the inhibitory effect of a trimeric aminopyrazole derivative allowed an estimation of the dissociation constant in the range of 10(-5) m. Finally, electrospray ionization mass spectrometry (ESI-MS) was used to determine the aggregation kinetics of Abeta-(1-40) in the absence and in the presence of the ligands. From the comparable decrease in Abeta monomer concentration, we conclude that these beta-sheet ligands do not prevent the initial oligomerization of monomeric Abeta but rather block further aggregation of spontaneously formed small oligomers. Together with the results from density gradient centrifugation and fluorescence correlation spectroscopy it is now possible to restrict the approximate size of soluble Abeta aggregates formed in the presence of both inhibitors from 3- to 15-mers.
DOI: 10.1074/jbc.M405914200
PubMed: 15322133
Affiliations:
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Le document en format XML
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(metabolism)</term><term>Protein Structure, Quaternary</term><term>Protein Structure, Secondary</term><term>Pyrazoles (chemistry)</term><term>Pyrazoles (metabolism)</term><term>Spectrometry, Fluorescence (methods)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Centrifugation en gradient de densité</term><term>Fragments peptidiques ()</term><term>Fragments peptidiques (génétique)</term><term>Fragments peptidiques (métabolisme)</term><term>Humains</term><term>Liaison hydrogène</term><term>Ligands</term><term>Maladie d'Alzheimer (anatomopathologie)</term><term>Maladie d'Alzheimer (métabolisme)</term><term>Modèles moléculaires</term><term>Peptides bêta-amyloïdes ()</term><term>Peptides bêta-amyloïdes (génétique)</term><term>Peptides bêta-amyloïdes (métabolisme)</term><term>Pyrazoles ()</term><term>Pyrazoles (métabolisme)</term><term>Spectrométrie de fluorescence ()</term><term>Structure moléculaire</term><term>Structure quaternaire des protéines</term><term>Structure secondaire des protéines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Amyloid beta-Peptides</term><term>Peptide Fragments</term><term>Pyrazoles</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Amyloid beta-Peptides</term><term>Peptide Fragments</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Maladie d'Alzheimer</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Fragments peptidiques</term><term>Peptides bêta-amyloïdes</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Alzheimer Disease</term><term>Amyloid beta-Peptides</term><term>Peptide Fragments</term><term>Pyrazoles</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Spectrometry, Fluorescence</term></keywords><keywords scheme="MESH" qualifier="métabolisme" 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protéines</term><term>Structure secondaire des protéines</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">A new concept is introduced for the rational design of beta-sheet ligands, which prevent protein aggregation. Oligomeric acylated aminopyrazoles with a donor-acceptor-donor (DAD) hydrogen bond pattern complementary to that of a beta-sheet efficiently block the solvent-exposed beta-sheet portions in Abeta-(1-40) and thereby prevent formation of insoluble protein aggregates. Density gradient centrifugation revealed that in the initial phase, the size of Abeta aggregates was efficiently kept between the trimeric and 15-meric state, whereas after 5 days an additional high molecular weight fraction appeared. With fluorescence correlation spectroscopy (FCS) exactly those two, i.e. a dimeric aminopyrazole with an oxalyl spacer and a trimeric head-to-tail connected aminopyrazole, of nine similar aminopyrazole ligands were identified as efficient aggregation retardants whose minimum energy conformations showed a perfect complementarity to a beta-sheet. The concentration dependence of the inhibitory effect of a trimeric aminopyrazole derivative allowed an estimation of the dissociation constant in the range of 10(-5) m. Finally, electrospray ionization mass spectrometry (ESI-MS) was used to determine the aggregation kinetics of Abeta-(1-40) in the absence and in the presence of the ligands. From the comparable decrease in Abeta monomer concentration, we conclude that these beta-sheet ligands do not prevent the initial oligomerization of monomeric Abeta but rather block further aggregation of spontaneously formed small oligomers. Together with the results from density gradient centrifugation and fluorescence correlation spectroscopy it is now possible to restrict the approximate size of soluble Abeta aggregates formed in the presence of both inhibitors from 3- to 15-mers.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><noCountry><name sortKey="Aschermann, Katja" sort="Aschermann, Katja" uniqKey="Aschermann K" first="Katja" last="Aschermann">Katja Aschermann</name><name sortKey="Feuerstein, Sophie" sort="Feuerstein, Sophie" uniqKey="Feuerstein S" first="Sophie" last="Feuerstein">Sophie Feuerstein</name><name sortKey="Linne, Uwe" sort="Linne, Uwe" uniqKey="Linne U" first="Uwe" last="Linne">Uwe Linne</name><name sortKey="Molt, Oliver" sort="Molt, Oliver" uniqKey="Molt O" first="Oliver" last="Molt">Oliver Molt</name><name sortKey="Nagel Steger, Luitgard" sort="Nagel Steger, Luitgard" uniqKey="Nagel Steger L" first="Luitgard" last="Nagel-Steger">Luitgard Nagel-Steger</name><name sortKey="Riesner, Detlev" sort="Riesner, Detlev" uniqKey="Riesner D" first="Detlev" last="Riesner">Detlev Riesner</name><name sortKey="Schrader, Thomas" sort="Schrader, Thomas" uniqKey="Schrader T" first="Thomas" last="Schrader">Thomas Schrader</name><name sortKey="Wehner, Markus" sort="Wehner, Markus" uniqKey="Wehner M" first="Markus" last="Wehner">Markus Wehner</name><name sortKey="Zadmard, Reza" sort="Zadmard, Reza" uniqKey="Zadmard R" first="Reza" last="Zadmard">Reza Zadmard</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Rzepecki, Petra" sort="Rzepecki, Petra" uniqKey="Rzepecki P" first="Petra" last="Rzepecki">Petra Rzepecki</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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