Plasma kallikrein cleaves and inactivates apelin-17: Palmitoyl- and PEG-extended apelin-17 analogs as metabolically stable blood pressure-lowering agents.
Identifieur interne : 000430 ( Main/Exploration ); précédent : 000429; suivant : 000431Plasma kallikrein cleaves and inactivates apelin-17: Palmitoyl- and PEG-extended apelin-17 analogs as metabolically stable blood pressure-lowering agents.
Auteurs : Conrad Fischer [Canada] ; Tess Lamer [Canada] ; Wang Wang [Canada] ; Shaun M K. Mckinnie [Canada] ; Xavier Iturrioz [France] ; Catherine Llorens-Cortes [France] ; Gavin Y. Oudit [Canada] ; John C. Vederas [Canada]Source :
- European journal of medicinal chemistry [ 1768-3254 ] ; 2019.
Descripteurs français
- KwdFr :
- MESH :
- métabolisme : Kallicréine plasmatique.
- Acides gras, Humains, Polyéthylène glycols, Pression sanguine, Protéolyse, Stabilité protéique.
English descriptors
- KwdEn :
- MESH :
- chemical , chemistry : Apelin, Fatty Acids, Polyethylene Glycols.
- chemical , metabolism : Apelin, Plasma Kallikrein.
- chemical , pharmacology : Apelin.
- drug effects : Blood Pressure.
- Humans, Protein Stability, Proteolysis.
Abstract
Apelins are human peptide hormones with various physiological activities, including the moderation of cardiovascular, renal, metabolic and neurological function. Their potency is dependent on and limited by proteolytic degradation in the circulatory system. Here we identify human plasma kallikrein (KLKB1) as a protease that cleaves the first three N-terminal amino acids (KFR) of apelin-17. The cleavage kinetics are similar to neprilysin (NEP), which cleaves within the critical 'RPRL'-motif thereby inactivating apelin. The resulting C-terminal 14-mer after KLKB1 cleavage has much lower biological activity, and the presence of its N-terminal basic arginine seems to negate the blood pressure lowering effect. Based on C-terminally engineered apelin analogs (A2), resistant to angiotensin converting enzyme 2 (ACE2), attachment of an N-terminal C16 fatty acid chain (PALMitoylation) or polyethylene glycol chain (PEGylation) minimizes KLKB1 cleavage of the 17-mers, thereby extending plasma half-life while fully retaining biological activity. The N-terminally PEGylated apelin-17(A2) is a highly protease resistant analog, with excellent apelin receptor activation and pronounced blood pressure lowering effect.
DOI: 10.1016/j.ejmech.2019.01.040
PubMed: 30690406
Affiliations:
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Electronic address: John.Vederas@ualberta.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2</wicri:regionArea><wicri:noRegion>T6G 2G2</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2019">2019</date><idno type="RBID">pubmed:30690406</idno><idno type="pmid">30690406</idno><idno type="doi">10.1016/j.ejmech.2019.01.040</idno><idno type="wicri:Area/PubMed/Corpus">000656</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000656</idno><idno type="wicri:Area/PubMed/Curation">000656</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000656</idno><idno type="wicri:Area/PubMed/Checkpoint">000428</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000428</idno><idno type="wicri:Area/Ncbi/Merge">002095</idno><idno type="wicri:Area/Ncbi/Curation">002095</idno><idno type="wicri:Area/Ncbi/Checkpoint">002095</idno><idno type="wicri:Area/Main/Merge">000433</idno><idno type="wicri:Area/Main/Curation">000430</idno><idno type="wicri:Area/Main/Exploration">000430</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Plasma kallikrein cleaves and inactivates apelin-17: Palmitoyl- and PEG-extended apelin-17 analogs as metabolically stable blood pressure-lowering agents.</title><author><name sortKey="Fischer, Conrad" sort="Fischer, Conrad" uniqKey="Fischer C" first="Conrad" last="Fischer">Conrad Fischer</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2</wicri:regionArea><wicri:noRegion>T6G 2G2</wicri:noRegion></affiliation></author><author><name sortKey="Lamer, Tess" sort="Lamer, Tess" uniqKey="Lamer T" first="Tess" last="Lamer">Tess Lamer</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2</wicri:regionArea><wicri:noRegion>T6G 2G2</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Wang" sort="Wang, Wang" uniqKey="Wang W" first="Wang" last="Wang">Wang Wang</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440-112 St. NW, Edmonton, Alberta, T6G 2B7, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440-112 St. NW, Edmonton, Alberta, T6G 2B7</wicri:regionArea><wicri:noRegion>T6G 2B7</wicri:noRegion></affiliation></author><author><name sortKey="Mckinnie, Shaun M K" sort="Mckinnie, Shaun M K" uniqKey="Mckinnie S" first="Shaun M K" last="Mckinnie">Shaun M K. Mckinnie</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2</wicri:regionArea><wicri:noRegion>T6G 2G2</wicri:noRegion></affiliation></author><author><name sortKey="Iturrioz, Xavier" sort="Iturrioz, Xavier" uniqKey="Iturrioz X" first="Xavier" last="Iturrioz">Xavier Iturrioz</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, INSERM, U1050, Paris, F-75005, France; Center for Interdisciplinary Research in Biology (CIRB), College de France, Paris, F-75005, France; CNRS, UMR 7241, Paris, F-75005, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, INSERM, U1050, Paris, F-75005, France; Center for Interdisciplinary Research in Biology (CIRB), College de France, Paris, F-75005, France; CNRS, UMR 7241, Paris, F-75005</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Llorens Cortes, Catherine" sort="Llorens Cortes, Catherine" uniqKey="Llorens Cortes C" first="Catherine" last="Llorens-Cortes">Catherine Llorens-Cortes</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, INSERM, U1050, Paris, F-75005, France; Center for Interdisciplinary Research in Biology (CIRB), College de France, Paris, F-75005, France; CNRS, UMR 7241, Paris, F-75005, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, INSERM, U1050, Paris, F-75005, France; Center for Interdisciplinary Research in Biology (CIRB), College de France, Paris, F-75005, France; CNRS, UMR 7241, Paris, F-75005</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Oudit, Gavin Y" sort="Oudit, Gavin Y" uniqKey="Oudit G" first="Gavin Y" last="Oudit">Gavin Y. Oudit</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440-112 St. NW, Edmonton, Alberta, T6G 2B7, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440-112 St. NW, Edmonton, Alberta, T6G 2B7</wicri:regionArea><wicri:noRegion>T6G 2B7</wicri:noRegion></affiliation></author><author><name sortKey="Vederas, John C" sort="Vederas, John C" uniqKey="Vederas J" first="John C" last="Vederas">John C. Vederas</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada. Electronic address: John.Vederas@ualberta.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2</wicri:regionArea><wicri:noRegion>T6G 2G2</wicri:noRegion></affiliation></author></analytic><series><title level="j">European journal of medicinal chemistry</title><idno type="eISSN">1768-3254</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Apelin (chemistry)</term><term>Apelin (metabolism)</term><term>Apelin (pharmacology)</term><term>Blood Pressure (drug effects)</term><term>Fatty Acids (chemistry)</term><term>Humans</term><term>Plasma Kallikrein (metabolism)</term><term>Polyethylene Glycols (chemistry)</term><term>Protein Stability</term><term>Proteolysis</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Acides gras ()</term><term>Humains</term><term>Kallicréine plasmatique (métabolisme)</term><term>Polyéthylène glycols ()</term><term>Pression sanguine ()</term><term>Protéolyse</term><term>Stabilité protéique</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Apelin</term><term>Fatty Acids</term><term>Polyethylene Glycols</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Apelin</term><term>Plasma Kallikrein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Apelin</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Blood Pressure</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Kallicréine plasmatique</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Humans</term><term>Protein Stability</term><term>Proteolysis</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Acides gras</term><term>Humains</term><term>Polyéthylène glycols</term><term>Pression sanguine</term><term>Protéolyse</term><term>Stabilité protéique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Apelins are human peptide hormones with various physiological activities, including the moderation of cardiovascular, renal, metabolic and neurological function. Their potency is dependent on and limited by proteolytic degradation in the circulatory system. Here we identify human plasma kallikrein (KLKB1) as a protease that cleaves the first three N-terminal amino acids (KFR) of apelin-17. The cleavage kinetics are similar to neprilysin (NEP), which cleaves within the critical 'RPRL'-motif thereby inactivating apelin. The resulting C-terminal 14-mer after KLKB1 cleavage has much lower biological activity, and the presence of its N-terminal basic arginine seems to negate the blood pressure lowering effect. Based on C-terminally engineered apelin analogs (A2), resistant to angiotensin converting enzyme 2 (ACE2), attachment of an N-terminal C16 fatty acid chain (PALMitoylation) or polyethylene glycol chain (PEGylation) minimizes KLKB1 cleavage of the 17-mers, thereby extending plasma half-life while fully retaining biological activity. The N-terminally PEGylated apelin-17(A2) is a highly protease resistant analog, with excellent apelin receptor activation and pronounced blood pressure lowering effect.</div></front></TEI><affiliations><list><country><li>Canada</li><li>France</li></country><region><li>Île-de-France</li></region></list><tree><country name="Canada"><noRegion><name sortKey="Fischer, Conrad" sort="Fischer, Conrad" uniqKey="Fischer C" first="Conrad" last="Fischer">Conrad Fischer</name></noRegion><name sortKey="Lamer, Tess" sort="Lamer, Tess" uniqKey="Lamer T" first="Tess" last="Lamer">Tess Lamer</name><name sortKey="Mckinnie, Shaun M K" sort="Mckinnie, Shaun M K" uniqKey="Mckinnie S" first="Shaun M K" last="Mckinnie">Shaun M K. Mckinnie</name><name sortKey="Oudit, Gavin Y" sort="Oudit, Gavin Y" uniqKey="Oudit G" first="Gavin Y" last="Oudit">Gavin Y. Oudit</name><name sortKey="Vederas, John C" sort="Vederas, John C" uniqKey="Vederas J" first="John C" last="Vederas">John C. Vederas</name><name sortKey="Wang, Wang" sort="Wang, Wang" uniqKey="Wang W" first="Wang" last="Wang">Wang Wang</name></country><country name="France"><region name="Île-de-France"><name sortKey="Iturrioz, Xavier" sort="Iturrioz, Xavier" uniqKey="Iturrioz X" first="Xavier" last="Iturrioz">Xavier Iturrioz</name></region><name sortKey="Llorens Cortes, Catherine" sort="Llorens Cortes, Catherine" uniqKey="Llorens Cortes C" first="Catherine" last="Llorens-Cortes">Catherine Llorens-Cortes</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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