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

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

Author Conceicao, Katia Autor UNIFESP Google Scholar
Magalhaes, Pedro R. Google Scholar
Campos, Sara R. R. Google Scholar
Domingues, Marco M. Google Scholar
Ramu, Vasanthakumar G. Google Scholar
Michalek, Matthias Google Scholar
Bertani, Philippe Google Scholar
Baptista, Antonio M. Google Scholar
Heras, Montserrat Google Scholar
Bardaji, Eduard R. Google Scholar
Bechinger, Burkhard Google Scholar
Ferreira, Monica Lopes Google Scholar
Castanho, Miguel A. R. B. Google Scholar
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.
Keywords Kyotorphin
Kyotorphin Amide
MicrocirculationMolecular-Dynamics Simulations
L-Arginine Kyotorphin
Intravital Microscopy
Peptide Drugs
Language English
Sponsor Fundacao para a Ciencia e Tecnologia (Portugal) [SFRH/BD/65709/2009, PTDC/BIA-PRO/104378/2008, PEst-OE/EQB/LA0004/2011]
Marie Curie IAPP
Marie Curie Industry-Academia Partnerships and Pathways (European Commission) [FP7-PEOPLE-2007-3-1-IAPP, 230654]
Deutsche Forschungsgemeinschaft
Agence Nationale de la Recherche
University of Strasbourg
Region Alsace
RTRA International Center of Frontier Research in Chemistry
Grant number Fundacao para a Ciencia e Tecnologia (Portugal): SFRH/BD/65709/2009
Fundacao para a Ciencia e Tecnologia (Portugal): PTDC/BIA-PRO/104378/2008
Fundacao para a Ciencia e Tecnologia (Portugal): PEst-OE/EQB/LA0004/2011
Marie Curie Industry-Academia Partnerships and Pathways (European Commission): FP7-PEOPLE-2007-3-1-IAPP. Project 230654
Date 2016
Published in Amino Acids. Wien, v. 48, n. 1, p. 307-318, 2016.
ISSN 0939-4451 (Sherpa/Romeo, impact factor)
Publisher Springer wien
Extent 307-318
Access rights Closed access
Type Article
Web of Science ID WOS:000369306900027

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