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Development and characterisation of a peptidergic N-and C-terminally stabilised mammalian NPY1R agonist which protects against diabetes induction.

Identifieur interne : 000112 ( Main/Exploration ); précédent : 000111; suivant : 000113

Development and characterisation of a peptidergic N-and C-terminally stabilised mammalian NPY1R agonist which protects against diabetes induction.

Auteurs : Ryan A. Lafferty [Royaume-Uni] ; Neil Tanday [Royaume-Uni] ; Peter R. Flatt [Royaume-Uni] ; Nigel Irwin [Royaume-Uni]

Source :

RBID : pubmed:32007578

Descripteurs français

English descriptors

Abstract

BACKGROUND

PYY (1-36) peptides from phylogenetically ancient fish, such as sea lamprey, have previously been shown to function as specific neuropeptide Y1 receptor (NPYR1) agonists. Although, sea lamprey PYY (1-36) is N-terminally stable, we reveal in this study that the peptide is subject to endopeptidase mediated C-terminal dipeptide degradation. In an attempt to prevent this, (d-Arg

METHODS

In vitro bioassays assessed enzymatic stability, insulinostatic activity as well as beta-cell anti-apoptotic actions of (d-Arg

RESULTS

(d-Arg

CONCLUSION

We present (d-Arg

GENERAL SIGNIFICANCE

Enzymatically stable, long-acting PYY (1-36) peptides highlight the therapeutic benefits of sustained activation of NPYR1's in diabetes.


DOI: 10.1016/j.bbagen.2020.129543
PubMed: 32007578


Affiliations:


Links toward previous steps (curation, corpus...)


Le document en format XML

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<term>Diabetes Mellitus, Experimental (metabolism)</term>
<term>Diabetes Mellitus, Experimental (prevention & control)</term>
<term>Fish Proteins (chemistry)</term>
<term>Fish Proteins (therapeutic use)</term>
<term>Hypoglycemic Agents (chemistry)</term>
<term>Hypoglycemic Agents (therapeutic use)</term>
<term>Insulin (metabolism)</term>
<term>Insulin-Secreting Cells (drug effects)</term>
<term>Insulin-Secreting Cells (metabolism)</term>
<term>Male (MeSH)</term>
<term>Mice (MeSH)</term>
<term>Peptides (chemistry)</term>
<term>Peptides (therapeutic use)</term>
<term>Petromyzon (MeSH)</term>
<term>Protective Agents (chemistry)</term>
<term>Protective Agents (therapeutic use)</term>
<term>Receptors, Neuropeptide Y (agonists)</term>
<term>Receptors, Neuropeptide Y (metabolism)</term>
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<term>Agents protecteurs (composition chimique)</term>
<term>Agents protecteurs (usage thérapeutique)</term>
<term>Animaux (MeSH)</term>
<term>Cellules à insuline (effets des médicaments et des substances chimiques)</term>
<term>Cellules à insuline (métabolisme)</term>
<term>Diabète expérimental (métabolisme)</term>
<term>Diabète expérimental (prévention et contrôle)</term>
<term>Diabète expérimental (traitement médicamenteux)</term>
<term>Hypoglycémiants (composition chimique)</term>
<term>Hypoglycémiants (usage thérapeutique)</term>
<term>Insuline (métabolisme)</term>
<term>Lignée cellulaire (MeSH)</term>
<term>Mâle (MeSH)</term>
<term>Peptides (composition chimique)</term>
<term>Peptides (usage thérapeutique)</term>
<term>Petromyzon (MeSH)</term>
<term>Protéines de poisson (composition chimique)</term>
<term>Protéines de poisson (usage thérapeutique)</term>
<term>Récepteur neuropeptide Y (agonistes)</term>
<term>Récepteur neuropeptide Y (métabolisme)</term>
<term>Souris (MeSH)</term>
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<term>Receptors, Neuropeptide Y</term>
</keywords>
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<term>Fish Proteins</term>
<term>Hypoglycemic Agents</term>
<term>Peptides</term>
<term>Protective Agents</term>
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<term>Récepteur neuropeptide Y</term>
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<term>Agents protecteurs</term>
<term>Hypoglycémiants</term>
<term>Peptides</term>
<term>Protéines de poisson</term>
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<term>Insulin-Secreting Cells</term>
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<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en">
<term>Diabetes Mellitus, Experimental</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr">
<term>Cellules à insuline</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en">
<term>Diabetes Mellitus, Experimental</term>
<term>Insulin</term>
<term>Insulin-Secreting Cells</term>
<term>Receptors, Neuropeptide Y</term>
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<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Cellules à insuline</term>
<term>Diabète expérimental</term>
<term>Insuline</term>
<term>Récepteur neuropeptide Y</term>
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<term>Diabetes Mellitus, Experimental</term>
</keywords>
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<term>Diabète expérimental</term>
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<term>Hypoglycemic Agents</term>
<term>Peptides</term>
<term>Protective Agents</term>
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<term>Hypoglycémiants</term>
<term>Peptides</term>
<term>Protéines de poisson</term>
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<term>Male</term>
<term>Mice</term>
<term>Petromyzon</term>
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<term>Animaux</term>
<term>Lignée cellulaire</term>
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<front>
<div type="abstract" xml:lang="en">
<p>
<b>BACKGROUND</b>
</p>
<p>PYY (1-36) peptides from phylogenetically ancient fish, such as sea lamprey, have previously been shown to function as specific neuropeptide Y1 receptor (NPYR1) agonists. Although, sea lamprey PYY (1-36) is N-terminally stable, we reveal in this study that the peptide is subject to endopeptidase mediated C-terminal dipeptide degradation. In an attempt to prevent this, (d-Arg</p>
</div>
<div type="abstract" xml:lang="en">
<p>
<b>METHODS</b>
</p>
<p>In vitro bioassays assessed enzymatic stability, insulinostatic activity as well as beta-cell anti-apoptotic actions of (d-Arg</p>
</div>
<div type="abstract" xml:lang="en">
<p>
<b>RESULTS</b>
</p>
<p>(d-Arg</p>
</div>
<div type="abstract" xml:lang="en">
<p>
<b>CONCLUSION</b>
</p>
<p>We present (d-Arg</p>
</div>
<div type="abstract" xml:lang="en">
<p>
<b>GENERAL SIGNIFICANCE</b>
</p>
<p>Enzymatically stable, long-acting PYY (1-36) peptides highlight the therapeutic benefits of sustained activation of NPYR1's in diabetes.</p>
</div>
</front>
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<Year>2020</Year>
<Month>10</Month>
<Day>19</Day>
</DateCompleted>
<DateRevised>
<Year>2020</Year>
<Month>10</Month>
<Day>19</Day>
</DateRevised>
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<ISSN IssnType="Electronic">1872-8006</ISSN>
<JournalIssue CitedMedium="Internet">
<Volume>1864</Volume>
<Issue>5</Issue>
<PubDate>
<Year>2020</Year>
<Month>05</Month>
</PubDate>
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<Title>Biochimica et biophysica acta. General subjects</Title>
<ISOAbbreviation>Biochim Biophys Acta Gen Subj</ISOAbbreviation>
</Journal>
<ArticleTitle>Development and characterisation of a peptidergic N-and C-terminally stabilised mammalian NPY1R agonist which protects against diabetes induction.</ArticleTitle>
<Pagination>
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<Abstract>
<AbstractText Label="BACKGROUND">PYY (1-36) peptides from phylogenetically ancient fish, such as sea lamprey, have previously been shown to function as specific neuropeptide Y1 receptor (NPYR1) agonists. Although, sea lamprey PYY (1-36) is N-terminally stable, we reveal in this study that the peptide is subject to endopeptidase mediated C-terminal dipeptide degradation. In an attempt to prevent this, (d-Arg
<sup>35</sup>
)-sea lamprey PYY (1-36) was developed.</AbstractText>
<AbstractText Label="METHODS">In vitro bioassays assessed enzymatic stability, insulinostatic activity as well as beta-cell anti-apoptotic actions of (d-Arg
<sup>35</sup>
)-sea lamprey PYY (1-36). Follow-up studies examined the impact of twice daily administration of sea lamprey PYY (1-36) or (d-Arg
<sup>35</sup>
)-sea lamprey PYY (1-36) in multiple low dose STZ-induced diabetic mice.</AbstractText>
<AbstractText Label="RESULTS">(d-Arg
<sup>35</sup>
)-sea lamprey PYY (1-36) was fully resistant to plasma enzymatic degradation. The peptide possessed similar significant insulinostatic, as well as positive anti-apoptotic biological actions, as the parent peptide. Sea lamprey PYY (1-36) and (d-Arg
<sup>35</sup>
)-sea lamprey PYY (1-36) delayed diabetes progression in STZ mice. Both treatment interventions induced a significant decrease in body weight, food and fluid intake as well as glucose and glucagon concentrations. In addition, glucose tolerance, plasma and pancreatic insulin were partially normalised. (d-Arg
<sup>35</sup>
)-sea lamprey PYY (1-36) was significantly more effective than sea lamprey PYY (1-36) in terms of enhancing glucose-stimulate insulin release. Both treatments improved pancreatic islet morphology, linked to decreased apoptosis of beta-cells.</AbstractText>
<AbstractText Label="CONCLUSION">We present (d-Arg
<sup>35</sup>
)-sea lamprey PYY (1-36) as the first-in-class N- and C-terminally stable PYY (1-36) peptide analogue.</AbstractText>
<AbstractText Label="GENERAL SIGNIFICANCE">Enzymatically stable, long-acting PYY (1-36) peptides highlight the therapeutic benefits of sustained activation of NPYR1's in diabetes.</AbstractText>
<CopyrightInformation>Copyright © 2020 Elsevier B.V. All rights reserved.</CopyrightInformation>
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</AffiliationInfo>
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</AffiliationInfo>
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</AffiliationInfo>
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<Initials>N</Initials>
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<Affiliation>SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland BT52 1SA, UK. Electronic address: n.irwin@ulster.ac.uk.</Affiliation>
</AffiliationInfo>
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<Month>01</Month>
<Day>30</Day>
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<QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName>
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<MeshHeading>
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<MeshHeading>
<DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName>
</MeshHeading>
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<QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName>
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<MeshHeading>
<DescriptorName UI="D048428" MajorTopicYN="N">Petromyzon</DescriptorName>
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<MeshHeading>
<DescriptorName UI="D020011" MajorTopicYN="N">Protective Agents</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D017476" MajorTopicYN="N">Receptors, Neuropeptide Y</DescriptorName>
<QualifierName UI="Q000819" MajorTopicYN="Y">agonists</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
</MeshHeadingList>
<KeywordList Owner="NOTNLM">
<Keyword MajorTopicYN="Y">Beta-cell</Keyword>
<Keyword MajorTopicYN="Y">Diabetes</Keyword>
<Keyword MajorTopicYN="Y">Enzymatic stability</Keyword>
<Keyword MajorTopicYN="Y">Peptide YY (PYY)</Keyword>
<Keyword MajorTopicYN="Y">Sea lamprey</Keyword>
</KeywordList>
<CoiStatement>Declaration of Competing Interest PRF and NI are named on patents filed by the University of Ulster for exploitation of peptide therapeutics.</CoiStatement>
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<Month>01</Month>
<Day>27</Day>
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<Month>01</Month>
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