Plasma kallikrein cleaves and inactivates apelin-17: Palmitoyl- and PEG-extended apelin-17 analogs as metabolically stable blood pressure-lowering agents.
Identifieur interne : 000656 ( PubMed/Corpus ); précédent : 000655; suivant : 000657Plasma kallikrein cleaves and inactivates apelin-17: Palmitoyl- and PEG-extended apelin-17 analogs as metabolically stable blood pressure-lowering agents.
Auteurs : Conrad Fischer ; Tess Lamer ; Wang Wang ; Shaun M K. Mckinnie ; Xavier Iturrioz ; Catherine Llorens-Cortes ; Gavin Y. Oudit ; John C. VederasSource :
- European journal of medicinal chemistry [ 1768-3254 ] ; 2019.
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
Links to Exploration step
pubmed:30690406Le document en format XML
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Mckinnie</name><affiliation><nlm:affiliation>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Iturrioz, Xavier" sort="Iturrioz, Xavier" uniqKey="Iturrioz X" first="Xavier" last="Iturrioz">Xavier Iturrioz</name><affiliation><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></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><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></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><nlm:affiliation>Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440-112 St. NW, Edmonton, Alberta, T6G 2B7, Canada.</nlm:affiliation></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><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></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></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><nlm:affiliation>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Lamer, Tess" sort="Lamer, Tess" uniqKey="Lamer T" first="Tess" last="Lamer">Tess Lamer</name><affiliation><nlm:affiliation>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Wang, Wang" sort="Wang, Wang" uniqKey="Wang W" first="Wang" last="Wang">Wang Wang</name><affiliation><nlm:affiliation>Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440-112 St. NW, Edmonton, Alberta, T6G 2B7, Canada.</nlm:affiliation></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><nlm:affiliation>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Iturrioz, Xavier" sort="Iturrioz, Xavier" uniqKey="Iturrioz X" first="Xavier" last="Iturrioz">Xavier Iturrioz</name><affiliation><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></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><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></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><nlm:affiliation>Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440-112 St. NW, Edmonton, Alberta, T6G 2B7, Canada.</nlm:affiliation></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><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></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="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" xml:lang="en"><term>Humans</term><term>Protein Stability</term><term>Proteolysis</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><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">30690406</PMID><DateCompleted><Year>2019</Year><Month>03</Month><Day>05</Day></DateCompleted><DateRevised><Year>2019</Year><Month>03</Month><Day>05</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1768-3254</ISSN><JournalIssue CitedMedium="Internet"><Volume>166</Volume><PubDate><Year>2019</Year><Month>Mar</Month><Day>15</Day></PubDate></JournalIssue><Title>European journal of medicinal chemistry</Title><ISOAbbreviation>Eur J Med Chem</ISOAbbreviation></Journal><ArticleTitle>Plasma kallikrein cleaves and inactivates apelin-17: Palmitoyl- and PEG-extended apelin-17 analogs as metabolically stable blood pressure-lowering agents.</ArticleTitle><Pagination><MedlinePgn>119-124</MedlinePgn></Pagination><ELocationID EIdType="pii" ValidYN="Y">S0223-5234(19)30050-9</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.ejmech.2019.01.040</ELocationID><Abstract><AbstractText>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.</AbstractText><CopyrightInformation>Copyright © 2019 Elsevier Masson SAS. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Fischer</LastName><ForeName>Conrad</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lamer</LastName><ForeName>Tess</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wang</LastName><ForeName>Wang</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440-112 St. NW, Edmonton, Alberta, T6G 2B7, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>McKinnie</LastName><ForeName>Shaun M K</ForeName><Initials>SMK</Initials><AffiliationInfo><Affiliation>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Iturrioz</LastName><ForeName>Xavier</ForeName><Initials>X</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Llorens-Cortes</LastName><ForeName>Catherine</ForeName><Initials>C</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Oudit</LastName><ForeName>Gavin Y</ForeName><Initials>GY</Initials><AffiliationInfo><Affiliation>Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440-112 St. NW, Edmonton, Alberta, T6G 2B7, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vederas</LastName><ForeName>John C</ForeName><Initials>JC</Initials><AffiliationInfo><Affiliation>Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada. Electronic address: John.Vederas@ualberta.ca.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2019</Year><Month>01</Month><Day>18</Day></ArticleDate></Article><MedlineJournalInfo><Country>France</Country><MedlineTA>Eur J Med Chem</MedlineTA><NlmUniqueID>0420510</NlmUniqueID><ISSNLinking>0223-5234</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000073861">Apelin</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D005227">Fatty Acids</NameOfSubstance></Chemical><Chemical><RegistryNumber>3WJQ0SDW1A</RegistryNumber><NameOfSubstance UI="D011092">Polyethylene Glycols</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.21.34</RegistryNumber><NameOfSubstance UI="D020842">Plasma Kallikrein</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000073861" MajorTopicYN="N">Apelin</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001794" MajorTopicYN="N">Blood Pressure</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005227" MajorTopicYN="N">Fatty Acids</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020842" MajorTopicYN="N">Plasma Kallikrein</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011092" MajorTopicYN="N">Polyethylene Glycols</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D055550" MajorTopicYN="N">Protein Stability</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D059748" MajorTopicYN="Y">Proteolysis</DescriptorName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Apelin</Keyword><Keyword MajorTopicYN="N">Cardiovascular disease</Keyword><Keyword MajorTopicYN="N">Peptide mimetics</Keyword><Keyword MajorTopicYN="N">Plasma kallikrein</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2018</Year><Month>08</Month><Day>20</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2019</Year><Month>01</Month><Day>12</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2019</Year><Month>01</Month><Day>17</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2019</Year><Month>1</Month><Day>29</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2019</Year><Month>3</Month><Day>6</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2019</Year><Month>1</Month><Day>29</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">30690406</ArticleId><ArticleId IdType="pii">S0223-5234(19)30050-9</ArticleId><ArticleId IdType="doi">10.1016/j.ejmech.2019.01.040</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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