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/Curation ); 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
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pubmed:30690406Le document en format XML
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<series><title level="j">European journal of medicinal chemistry</title>
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<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>
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<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>
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<term>Protein Stability</term>
<term>Proteolysis</term>
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<term>Humains</term>
<term>Polyéthylène glycols</term>
<term>Pression sanguine</term>
<term>Protéolyse</term>
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<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>
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