Design and in vitro characterization of PAC1/VPAC1-selective agonists with potent neuroprotective effects
Identifieur interne : 000173 ( France/Analysis ); précédent : 000172; suivant : 000174Design and in vitro characterization of PAC1/VPAC1-selective agonists with potent neuroprotective effects
Auteurs : Ngoc-Duc Doan [Canada] ; Steve Bourgault [Canada] ; Agnieszka Dejda [Canada] ; Myriam Letourneau [Canada] ; Michel Detheux [Belgique] ; David Vaudry [Canada, France] ; Hubert Vaudry [Canada, France] ; David Chatenet [Canada] ; Alain Fournier [Canada]Source :
- Biochemical pharmacology [ 0006-2952 ] ; 2011.
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- Pascal (Inist)
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Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide that exerts a large array of actions in the central nervous system and periphery. Through the activation of PAC1 and VPAC1, PACAP is able to exert neuroprotective, as well as anti-inflammatory effects, two phenomena involved in the pathogenesis and the progression of neurodegenerative diseases. The aim of the current study was to provide insights into the molecular arrangement of the amino terminus of PACAP and to develop new potent and selective PAC1/VPAC1 agonists promoting neuronal survival. We have synthesized a series of PACAP derivatives and measured their binding affinity and their ability to induce intracellular calcium mobilization for each receptor, i.e. PAC1, VPAC1, and VPAC2. Ultimately, analogs with an improved pharmacological profile were evaluated in an in vitro model of neuronal loss. Results showed that introduction of a hydroxyproline or an alanine moiety, respectively, at position 2 or 7 generated derivatives without significant VPAC2 agonistic activity. Moreover, the structure-activity relationship study suggests the presence of common (Asx-turn like) and distinct (different N-capping type) secondary structures that might be responsible for receptor recognition, selectivity and activation. Finally, evaluation of the neuroprotective activity of [Ala7]PACAP27 and [Hyp2]PACAP27 demonstrated their ability to protect potently human dopaminergic SH-SY5Y neuroblasts against the toxicity of MPP+, in pre- and co-treatment experiments. These new pharmacological and structural data should prove useful for the rational design of PACAP-derived compounds that could be putative therapeutic agents for the treatment of neurodegenerative diseases.
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INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Laboratoire International Associé Samuel de Champlain INSERM - INRS</wicri:noRegion></affiliation></author><author><name sortKey="Bourgault, Steve" sort="Bourgault, Steve" uniqKey="Bourgault S" first="Steve" last="Bourgault">Steve Bourgault</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Québec H7V 1B7</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Laboratoire International Associé Samuel de Champlain INSERM - INRS</wicri:noRegion></affiliation></author><author><name sortKey="Dejda, Agnieszka" sort="Dejda, Agnieszka" uniqKey="Dejda A" first="Agnieszka" last="Dejda">Agnieszka Dejda</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Québec H7V 1B7</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Laboratoire International Associé Samuel de Champlain INSERM - INRS</wicri:noRegion></affiliation></author><author><name sortKey="Letourneau, Myriam" sort="Letourneau, Myriam" uniqKey="Letourneau M" first="Myriam" last="Letourneau">Myriam Letourneau</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Québec H7V 1B7</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - 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INRS</wicri:noRegion></affiliation><affiliation wicri:level="4"><inist:fA14 i1="04"><s1>INSERM-U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, IFRMP 23, Université de Rouen</s1><s2>76821 Mont-Saint-Aignan</s2><s3>FRA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>76821 Mont-Saint-Aignan</wicri:noRegion><wicri:noRegion>Université de Rouen</wicri:noRegion><placeName><settlement type="city">Rouen</settlement><region type="region" nuts="2">Région Normandie</region><region type="old region" nuts="2">Haute-Normandie</region></placeName><orgName type="university">Université de Rouen</orgName></affiliation></author><author><name sortKey="Vaudry, Hubert" sort="Vaudry, Hubert" uniqKey="Vaudry H" first="Hubert" last="Vaudry">Hubert Vaudry</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Laboratoire International Associé Samuel de Champlain INSERM - INRS</wicri:noRegion></affiliation><affiliation wicri:level="4"><inist:fA14 i1="04"><s1>INSERM-U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, IFRMP 23, Université de Rouen</s1><s2>76821 Mont-Saint-Aignan</s2><s3>FRA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>76821 Mont-Saint-Aignan</wicri:noRegion><wicri:noRegion>Université de Rouen</wicri:noRegion><placeName><settlement type="city">Rouen</settlement><region type="region" nuts="2">Région Normandie</region><region type="old region" nuts="2">Haute-Normandie</region></placeName><orgName type="university">Université de Rouen</orgName></affiliation></author><author><name sortKey="Chatenet, David" sort="Chatenet, David" uniqKey="Chatenet D" first="David" last="Chatenet">David Chatenet</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Québec H7V 1B7</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Laboratoire International Associé Samuel de Champlain INSERM - INRS</wicri:noRegion></affiliation></author><author><name sortKey="Fournier, Alain" sort="Fournier, Alain" uniqKey="Fournier A" first="Alain" last="Fournier">Alain Fournier</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Québec H7V 1B7</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Laboratoire International Associé Samuel de Champlain INSERM - INRS</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Biochemical pharmacology</title><title level="j" type="abbreviated">Biochem. pharmacol.</title><idno type="ISSN">0006-2952</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Biochemical pharmacology</title><title level="j" type="abbreviated">Biochem. pharmacol.</title><idno type="ISSN">0006-2952</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Agonist</term><term>Characterization</term><term>In vitro</term><term>Neuroprotection</term><term>Neuroprotective agent</term><term>Parkinson disease</term><term>Pituitary adenylate cyclase activating peptide</term><term>Selectivity</term><term>Structure activity relation</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>In vitro</term><term>Caractérisation</term><term>Agoniste</term><term>Neuroprotection</term><term>Neuroprotecteur</term><term>Peptide PACAP</term><term>Relation structure activité</term><term>Sélectivité</term><term>Maladie de Parkinson</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide that exerts a large array of actions in the central nervous system and periphery. Through the activation of PAC1 and VPAC1, PACAP is able to exert neuroprotective, as well as anti-inflammatory effects, two phenomena involved in the pathogenesis and the progression of neurodegenerative diseases. The aim of the current study was to provide insights into the molecular arrangement of the amino terminus of PACAP and to develop new potent and selective PAC1/VPAC1 agonists promoting neuronal survival. We have synthesized a series of PACAP derivatives and measured their binding affinity and their ability to induce intracellular calcium mobilization for each receptor, i.e. PAC1, VPAC1, and VPAC2. Ultimately, analogs with an improved pharmacological profile were evaluated in an in vitro model of neuronal loss. Results showed that introduction of a hydroxyproline or an alanine moiety, respectively, at position 2 or 7 generated derivatives without significant VPAC2 agonistic activity. Moreover, the structure-activity relationship study suggests the presence of common (Asx-turn like) and distinct (different N-capping type) secondary structures that might be responsible for receptor recognition, selectivity and activation. Finally, evaluation of the neuroprotective activity of [Ala<sup>7</sup>]PACAP27 and [Hyp<sup>2</sup>]PACAP27 demonstrated their ability to protect potently human dopaminergic SH-SY5Y neuroblasts against the toxicity of MPP<sup>+</sup>, in pre- and co-treatment experiments. These new pharmacological and structural data should prove useful for the rational design of PACAP-derived compounds that could be putative therapeutic agents for the treatment of neurodegenerative diseases.</div></front></TEI><affiliations><list><country><li>Belgique</li><li>Canada</li><li>France</li></country><region><li>Haute-Normandie</li><li>Région Normandie</li></region><settlement><li>Rouen</li></settlement><orgName><li>Université de Rouen</li></orgName></list><tree><country name="Canada"><noRegion><name sortKey="Doan, Ngoc Duc" sort="Doan, Ngoc Duc" uniqKey="Doan N" first="Ngoc-Duc" last="Doan">Ngoc-Duc Doan</name></noRegion><name sortKey="Bourgault, Steve" sort="Bourgault, Steve" uniqKey="Bourgault S" first="Steve" last="Bourgault">Steve Bourgault</name><name sortKey="Bourgault, Steve" sort="Bourgault, Steve" uniqKey="Bourgault S" first="Steve" last="Bourgault">Steve Bourgault</name><name sortKey="Chatenet, David" sort="Chatenet, David" uniqKey="Chatenet D" first="David" last="Chatenet">David Chatenet</name><name sortKey="Chatenet, David" sort="Chatenet, David" uniqKey="Chatenet D" first="David" last="Chatenet">David Chatenet</name><name sortKey="Dejda, Agnieszka" sort="Dejda, Agnieszka" uniqKey="Dejda A" first="Agnieszka" last="Dejda">Agnieszka Dejda</name><name sortKey="Dejda, Agnieszka" sort="Dejda, Agnieszka" uniqKey="Dejda A" first="Agnieszka" last="Dejda">Agnieszka Dejda</name><name sortKey="Doan, Ngoc Duc" sort="Doan, Ngoc Duc" uniqKey="Doan N" first="Ngoc-Duc" last="Doan">Ngoc-Duc Doan</name><name sortKey="Fournier, Alain" sort="Fournier, Alain" uniqKey="Fournier A" first="Alain" last="Fournier">Alain Fournier</name><name sortKey="Fournier, Alain" sort="Fournier, Alain" uniqKey="Fournier A" first="Alain" last="Fournier">Alain Fournier</name><name sortKey="Letourneau, Myriam" sort="Letourneau, Myriam" uniqKey="Letourneau M" first="Myriam" last="Letourneau">Myriam Letourneau</name><name sortKey="Letourneau, Myriam" sort="Letourneau, Myriam" uniqKey="Letourneau M" first="Myriam" last="Letourneau">Myriam Letourneau</name><name sortKey="Vaudry, David" sort="Vaudry, David" uniqKey="Vaudry D" first="David" last="Vaudry">David Vaudry</name><name sortKey="Vaudry, Hubert" sort="Vaudry, Hubert" uniqKey="Vaudry H" first="Hubert" last="Vaudry">Hubert Vaudry</name></country><country name="Belgique"><noRegion><name sortKey="Detheux, Michel" sort="Detheux, Michel" uniqKey="Detheux M" first="Michel" last="Detheux">Michel Detheux</name></noRegion></country><country name="France"><region name="Région Normandie"><name sortKey="Vaudry, David" sort="Vaudry, David" uniqKey="Vaudry D" first="David" last="Vaudry">David Vaudry</name></region><name sortKey="Vaudry, Hubert" sort="Vaudry, Hubert" uniqKey="Vaudry H" first="Hubert" last="Vaudry">Hubert Vaudry</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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