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The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: Insights of a lipid-mediated mechanism

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

Marie Curie Industry-Academia Partnerships and Pathways (European Commission) is acknowledged for funding (FP7-PEOPLE-2007-3-1-IAPP. Project 230654)

© Amino Acids, 2016, vol. 48, núm. 1, p. 307-318

Springer Verlag

Author: Conceição, Katia
Magalhães, Pedro R.
Campos, Sara R R
Domingues, Marco M.
Ramu, Vasanthakumar Ganga
Michalek, Matthias
Bertani, Philippe
Baptista, António M.
Heras i Corominas, Montserrat
Bardají Rodríguez, Eduard
Bechinger, Burkhard
Ferreira, Mônica Lopes
Castanho, Miguel Augusto Rico Botas
Date: 2016 January 1
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
Marie Curie Industry-Academia Partnerships and Pathways (European Commission) is acknowledged for funding (FP7-PEOPLE-2007-3-1-IAPP. Project 230654)
Format: application/pdf
ISSN: 0939-4451 (versió paper)
1438-2199 (versió electrònica)
Document access: http://hdl.handle.net/10256/13191
Language: eng
Publisher: Springer Verlag
Collection: Reproducció digital del document publicat a: http://dx.doi.org/10.1007/s00726-015-2088-9
Articles publicats (D-Q)
info:eu-repo/grantAgreement/EC/FP7/230654
Is part of: © Amino Acids, 2016, vol. 48, núm. 1, p. 307-318
Rights: Tots els drets reservats
Subject: Analgèsics
Analgesics
Microcirculació
Microcirculation
Title: The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: Insights of a lipid-mediated mechanism
Type: info:eu-repo/semantics/article
Repository: DUGiDocs

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