The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: Insights of a lipid-mediated mechanism
dc.contributor.author
dc.date.accessioned
2016-11-22T09:32:02Z
dc.date.available
2016-11-22T09:32:02Z
dc.date.issued
2016-01-01
dc.identifier.issn
0939-4451
dc.identifier.uri
dc.description.abstract
Recently, a designed class of efficient analgesic drugs derived from an endogenous neuropeptide, kyotorphin (KTP, Tyr-Arg) combining C-terminal amidation (KTP-NH2) and N-terminal conjugation to ibuprofen (Ib), IbKTP-NH2, was developed. The Ib moiety is an enhancer of KTP-NH2 analgesic action. In the present study, we have tested the hypothesis that KTP-NH2 is an enhancer of the Ib anti-inflammatory action. Moreover, the impact of the IbKTP-NH2 conjugation on microcirculation was also evaluated by a unified approach based on intravital microscopy in the murine cremasteric muscle. Our data show that KTP-NH2 and conjugates do not cause damage on microcirculatory environment and efficiently decrease the number of leukocyte rolling induced by lipopolysaccharide (LPS). Isothermal titration calorimetry showed that the drugs bind to LPS directly thus contributing to LPS aggregation and subsequent elimination. In a parallel study, molecular dynamics simulations and NMR data showed that the IbKTP-NH2 tandem adopts a preferential "stretched" conformation in lipid bilayers and micelles, with the simulations indicating that the Ib moiety is anchored in the hydrophobic core, which explains the improved partition of IbKTP-NH2 to membranes and the permeability of lipid bilayers to this conjugate relative to KTP-NH2. The ability to bind glycolipids concomitant to the anchoring in the lipid membranes through the Ib residue explains the analgesic potency of IbKTP-NH2 given the enriched glycocalyx of the blood-brain barrier cells. Accumulation of IbKTP-NH2 in the membrane favors both direct permeation and local interaction with putative receptors as the location of the KTP-NH2 residue of IbKTP-NH2 and free KTP-NH2 in lipid membranes is the same
dc.description.sponsorship
Marie Curie Industry-Academia Partnerships and Pathways (European Commission) is acknowledged for funding (FP7-PEOPLE-2007-3-1-IAPP. Project 230654)
dc.format.mimetype
application/pdf
dc.language.iso
eng
dc.publisher
Springer Verlag
dc.relation.isformatof
Reproducció digital del document publicat a: http://dx.doi.org/10.1007/s00726-015-2088-9
dc.relation.ispartof
© Amino Acids, 2016, vol. 48, núm. 1, p. 307-318
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Articles publicats (D-Q)
dc.rights
Tots els drets reservats
dc.subject
dc.title
The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: Insights of a lipid-mediated mechanism
dc.type
info:eu-repo/semantics/article
dc.rights.accessRights
info:eu-repo/semantics/embargoedAccess
dc.embargo.terms
Cap
dc.date.embargoEndDate
info:eu-repo/date/embargoEnd/2026-01-01
dc.relation.projectID
info:eu-repo/grantAgreement/EC/FP7/230654/EU/Selected peptides as drug candidates directed to pain and neurodegeneration/PEP2BRAIN
dc.type.version
info:eu-repo/semantics/publishedVersion
dc.identifier.doi
dc.identifier.idgrec
024541
dc.relation.FundingProgramme
dc.relation.ProjectAcronym
dc.identifier.eissn
1438-2199