Design, synthesis and anti-HIV evaluation of novel diarylpyridine derivatives targeting the entrance channel of NNRTI binding pocket.
Identifieur interne : 001052 ( Main/Exploration ); précédent : 001051; suivant : 001053Design, synthesis and anti-HIV evaluation of novel diarylpyridine derivatives targeting the entrance channel of NNRTI binding pocket.
Auteurs : Jiapei Yang [République populaire de Chine] ; Wenmin Chen [République populaire de Chine] ; Dongwei Kang [République populaire de Chine] ; Xueyi Lu [République populaire de Chine] ; Xiao Li [République populaire de Chine] ; Zhaoqiang Liu [République populaire de Chine] ; Boshi Huang [République populaire de Chine] ; Dirk Daelemans [Belgique] ; Christophe Pannecouque [Belgique] ; Erik De Clercq [Belgique] ; Peng Zhan [République populaire de Chine] ; Xinyong Liu [République populaire de Chine]Source :
- European journal of medicinal chemistry [ 1768-3254 ] ; 2016.
Descripteurs français
- KwdFr :
- Agents antiVIH (), Agents antiVIH (pharmacologie), Agents antiVIH (synthèse chimique), Conception de médicament, Humains, Infections à VIH (traitement médicamenteux), Infections à VIH (virologie), Inhibiteurs de la transcriptase inverse (), Inhibiteurs de la transcriptase inverse (pharmacologie), Inhibiteurs de la transcriptase inverse (synthèse chimique), Mutation ponctuelle, Pyridines (), Pyridines (pharmacologie), Pyridines (synthèse chimique), Relation structure-activité, Simulation de docking moléculaire, Sites de fixation (), Transcriptase inverse du VIH (antagonistes et inhibiteurs), Transcriptase inverse du VIH (génétique), Transcriptase inverse du VIH (métabolisme), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (enzymologie), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (génétique).
- MESH :
- antagonistes et inhibiteurs : Transcriptase inverse du VIH.
- enzymologie : VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
- génétique : Transcriptase inverse du VIH, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
- métabolisme : Transcriptase inverse du VIH.
- pharmacologie : Agents antiVIH, Inhibiteurs de la transcriptase inverse, Pyridines.
- synthèse chimique : Agents antiVIH, Inhibiteurs de la transcriptase inverse, Pyridines.
- traitement médicamenteux : Infections à VIH.
- virologie : Infections à VIH.
- Agents antiVIH, Conception de médicament, Humains, Inhibiteurs de la transcriptase inverse, Mutation ponctuelle, Pyridines, Relation structure-activité, Simulation de docking moléculaire, Sites de fixation, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
English descriptors
- KwdEn :
- Anti-HIV Agents (chemical synthesis), Anti-HIV Agents (chemistry), Anti-HIV Agents (pharmacology), Binding Sites (drug effects), Drug Design, HIV Infections (drug therapy), HIV Infections (virology), HIV Reverse Transcriptase (antagonists & inhibitors), HIV Reverse Transcriptase (genetics), HIV Reverse Transcriptase (metabolism), HIV-1 (drug effects), HIV-1 (enzymology), HIV-1 (genetics), Humans, Molecular Docking Simulation, Point Mutation, Pyridines (chemical synthesis), Pyridines (chemistry), Pyridines (pharmacology), Reverse Transcriptase Inhibitors (chemical synthesis), Reverse Transcriptase Inhibitors (chemistry), Reverse Transcriptase Inhibitors (pharmacology), Structure-Activity Relationship.
- MESH :
- chemical , antagonists & inhibitors : HIV Reverse Transcriptase.
- chemical , chemical synthesis : Anti-HIV Agents, Pyridines, Reverse Transcriptase Inhibitors.
- chemical , chemistry : Anti-HIV Agents, Pyridines, Reverse Transcriptase Inhibitors.
- chemical , genetics : HIV Reverse Transcriptase.
- chemical , metabolism : HIV Reverse Transcriptase.
- chemical , pharmacology : Anti-HIV Agents, Pyridines, Reverse Transcriptase Inhibitors.
- drug effects : Binding Sites, HIV-1.
- drug therapy : HIV Infections.
- enzymology : HIV-1.
- genetics : HIV-1.
- virology : HIV Infections.
- Drug Design, Humans, Molecular Docking Simulation, Point Mutation, Structure-Activity Relationship.
Abstract
The development of novel NNRTIs with activity against variants of HIV-1RT is crucial for overcoming treatment failure. In the present study, a series of novel 6-substituted diarylpyridine derivatives targeting the entrance channel of the NNIBP of RT were designed through a molecular hybridization strategy. Encouragingly, these new diarylpyridine derivatives were found to be active against wild-type (WT) HIV-1 with an EC50 values ranging from 0.035 μM to 1.99 μM. Nearly half of them exhibited more potent inhibitory activities in cellular assays than the control drug nevirapine (NVP). Notably, three most promising compounds If (EC50 = 35 nM), Ia (EC50 = 43 nM) and IIa (EC50 = 41 nM) showed high potency against WT and were comparable to the reference drug delavirdine (DLV) (EC50 = 33 nM). Moreover, compounds Ib, IIb and IIh displayed effective activity against the most common clinically observed single and double-mutated HIV-1 strains in micromolar concentrations. In particular, the inhibition of IIb against the K103N mutation (EC50 = 49 nM), which confers resistance to a wide variety of NNRTIs, was about 140 times more effective than NVP (EC50 = 6.78 μM), 50 times more than DLV (EC50 = 2.48 μM) and about 3 times more than EFV (EC50 = 0.12 μM), indicating that the newly designed compounds have great potential to be further developed as new anti-HIV-1 agents. Preliminary structure-activity relationships (SARs) and molecular modeling of the new diarylpyridine derivatives were discussed in detail.
DOI: 10.1016/j.ejmech.2015.11.039
PubMed: 26802545
Affiliations:
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xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Wenmin" sort="Chen, Wenmin" uniqKey="Chen W" first="Wenmin" last="Chen">Wenmin Chen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Kang, Dongwei" sort="Kang, Dongwei" uniqKey="Kang D" first="Dongwei" last="Kang">Dongwei Kang</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Lu, Xueyi" sort="Lu, Xueyi" uniqKey="Lu X" first="Xueyi" last="Lu">Xueyi Lu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Li, Xiao" sort="Li, Xiao" uniqKey="Li X" first="Xiao" last="Li">Xiao Li</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Liu, Zhaoqiang" sort="Liu, Zhaoqiang" uniqKey="Liu Z" first="Zhaoqiang" last="Liu">Zhaoqiang Liu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Huang, Boshi" sort="Huang, Boshi" uniqKey="Huang B" first="Boshi" last="Huang">Boshi Huang</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Daelemans, Dirk" sort="Daelemans, Dirk" uniqKey="Daelemans D" first="Dirk" last="Daelemans">Dirk Daelemans</name><affiliation wicri:level="1"><nlm:affiliation>Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven</wicri:regionArea><wicri:noRegion>B-3000 Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Pannecouque, Christophe" sort="Pannecouque, Christophe" uniqKey="Pannecouque C" first="Christophe" last="Pannecouque">Christophe Pannecouque</name><affiliation wicri:level="1"><nlm:affiliation>Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven</wicri:regionArea><wicri:noRegion>B-3000 Leuven</wicri:noRegion></affiliation></author><author><name sortKey="De Clercq, Erik" sort="De Clercq, Erik" uniqKey="De Clercq E" first="Erik" last="De Clercq">Erik De Clercq</name><affiliation wicri:level="1"><nlm:affiliation>Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven</wicri:regionArea><wicri:noRegion>B-3000 Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Zhan, Peng" sort="Zhan, Peng" uniqKey="Zhan P" first="Peng" last="Zhan">Peng Zhan</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Liu, Xinyong" sort="Liu, Xinyong" uniqKey="Liu X" first="Xinyong" last="Liu">Xinyong Liu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author></analytic><series><title level="j">European journal of medicinal chemistry</title><idno type="eISSN">1768-3254</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Anti-HIV Agents (chemical synthesis)</term><term>Anti-HIV Agents (chemistry)</term><term>Anti-HIV Agents (pharmacology)</term><term>Binding Sites (drug effects)</term><term>Drug Design</term><term>HIV Infections (drug therapy)</term><term>HIV Infections (virology)</term><term>HIV Reverse Transcriptase (antagonists & inhibitors)</term><term>HIV Reverse Transcriptase (genetics)</term><term>HIV Reverse Transcriptase (metabolism)</term><term>HIV-1 (drug effects)</term><term>HIV-1 (enzymology)</term><term>HIV-1 (genetics)</term><term>Humans</term><term>Molecular Docking Simulation</term><term>Point Mutation</term><term>Pyridines (chemical synthesis)</term><term>Pyridines (chemistry)</term><term>Pyridines (pharmacology)</term><term>Reverse Transcriptase Inhibitors (chemical synthesis)</term><term>Reverse Transcriptase Inhibitors (chemistry)</term><term>Reverse Transcriptase Inhibitors (pharmacology)</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Agents antiVIH ()</term><term>Agents antiVIH (pharmacologie)</term><term>Agents antiVIH (synthèse chimique)</term><term>Conception de médicament</term><term>Humains</term><term>Infections à VIH (traitement médicamenteux)</term><term>Infections à VIH (virologie)</term><term>Inhibiteurs de la transcriptase inverse ()</term><term>Inhibiteurs de la transcriptase inverse (pharmacologie)</term><term>Inhibiteurs de la transcriptase inverse (synthèse chimique)</term><term>Mutation ponctuelle</term><term>Pyridines ()</term><term>Pyridines (pharmacologie)</term><term>Pyridines (synthèse chimique)</term><term>Relation structure-activité</term><term>Simulation de docking moléculaire</term><term>Sites de fixation ()</term><term>Transcriptase inverse du VIH (antagonistes et inhibiteurs)</term><term>Transcriptase inverse du VIH (génétique)</term><term>Transcriptase inverse du VIH (métabolisme)</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (enzymologie)</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (génétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>HIV Reverse Transcriptase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Anti-HIV Agents</term><term>Pyridines</term><term>Reverse Transcriptase Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Anti-HIV Agents</term><term>Pyridines</term><term>Reverse Transcriptase Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>HIV Reverse Transcriptase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>HIV Reverse Transcriptase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-HIV Agents</term><term>Pyridines</term><term>Reverse Transcriptase Inhibitors</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Transcriptase inverse du VIH</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Binding Sites</term><term>HIV-1</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>HIV Infections</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>HIV-1</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>HIV-1</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Transcriptase inverse du VIH</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Transcriptase inverse du VIH</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Agents antiVIH</term><term>Inhibiteurs de la transcriptase inverse</term><term>Pyridines</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Agents antiVIH</term><term>Inhibiteurs de la transcriptase inverse</term><term>Pyridines</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Infections à VIH</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Infections à VIH</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>HIV Infections</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Drug Design</term><term>Humans</term><term>Molecular Docking Simulation</term><term>Point Mutation</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Agents antiVIH</term><term>Conception de médicament</term><term>Humains</term><term>Inhibiteurs de la transcriptase inverse</term><term>Mutation ponctuelle</term><term>Pyridines</term><term>Relation structure-activité</term><term>Simulation de docking moléculaire</term><term>Sites de fixation</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The development of novel NNRTIs with activity against variants of HIV-1RT is crucial for overcoming treatment failure. In the present study, a series of novel 6-substituted diarylpyridine derivatives targeting the entrance channel of the NNIBP of RT were designed through a molecular hybridization strategy. Encouragingly, these new diarylpyridine derivatives were found to be active against wild-type (WT) HIV-1 with an EC50 values ranging from 0.035 μM to 1.99 μM. Nearly half of them exhibited more potent inhibitory activities in cellular assays than the control drug nevirapine (NVP). Notably, three most promising compounds If (EC50 = 35 nM), Ia (EC50 = 43 nM) and IIa (EC50 = 41 nM) showed high potency against WT and were comparable to the reference drug delavirdine (DLV) (EC50 = 33 nM). Moreover, compounds Ib, IIb and IIh displayed effective activity against the most common clinically observed single and double-mutated HIV-1 strains in micromolar concentrations. In particular, the inhibition of IIb against the K103N mutation (EC50 = 49 nM), which confers resistance to a wide variety of NNRTIs, was about 140 times more effective than NVP (EC50 = 6.78 μM), 50 times more than DLV (EC50 = 2.48 μM) and about 3 times more than EFV (EC50 = 0.12 μM), indicating that the newly designed compounds have great potential to be further developed as new anti-HIV-1 agents. Preliminary structure-activity relationships (SARs) and molecular modeling of the new diarylpyridine derivatives were discussed in detail. </div></front></TEI><affiliations><list><country><li>Belgique</li><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Yang, Jiapei" sort="Yang, Jiapei" uniqKey="Yang J" first="Jiapei" last="Yang">Jiapei Yang</name></noRegion><name sortKey="Chen, Wenmin" sort="Chen, Wenmin" uniqKey="Chen W" first="Wenmin" last="Chen">Wenmin Chen</name><name sortKey="Huang, Boshi" sort="Huang, Boshi" uniqKey="Huang B" first="Boshi" last="Huang">Boshi Huang</name><name sortKey="Kang, Dongwei" sort="Kang, Dongwei" uniqKey="Kang D" first="Dongwei" last="Kang">Dongwei Kang</name><name sortKey="Li, Xiao" sort="Li, Xiao" uniqKey="Li X" first="Xiao" last="Li">Xiao Li</name><name sortKey="Liu, Xinyong" sort="Liu, Xinyong" uniqKey="Liu X" first="Xinyong" last="Liu">Xinyong Liu</name><name sortKey="Liu, Zhaoqiang" sort="Liu, Zhaoqiang" uniqKey="Liu Z" first="Zhaoqiang" last="Liu">Zhaoqiang Liu</name><name sortKey="Lu, Xueyi" sort="Lu, Xueyi" uniqKey="Lu X" first="Xueyi" last="Lu">Xueyi Lu</name><name sortKey="Zhan, Peng" sort="Zhan, Peng" uniqKey="Zhan P" first="Peng" last="Zhan">Peng Zhan</name></country><country name="Belgique"><noRegion><name sortKey="Daelemans, Dirk" sort="Daelemans, Dirk" uniqKey="Daelemans D" first="Dirk" last="Daelemans">Dirk Daelemans</name></noRegion><name sortKey="De Clercq, Erik" sort="De Clercq, Erik" uniqKey="De Clercq E" first="Erik" last="De Clercq">Erik De Clercq</name><name sortKey="Pannecouque, Christophe" sort="Pannecouque, Christophe" uniqKey="Pannecouque C" first="Christophe" last="Pannecouque">Christophe Pannecouque</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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