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Chemical conjugation of the neuropeptide kyotorphin and ibuprofen enhances brain targeting and analgesia

The pharmaceutical potential of natural analgesic peptides is mainly hampered by their inability to cross the blood-brain barrier, BBB. Increasing peptide-cell membrane affinity through drug design is a promising strategy to overcome this limitation. To address this challenge, we grafted ibuprofen (IBP), a nonsteroidal anti-inflammatory drug, to kyotorphin (l-Tyr-l-Arg, KTP), an analgesic neuropeptide unable to cross BBB. Two new KTP derivatives, IBP-KTP (IbKTP-OH) and IBP-KTP-amide (IbKTP-NH 2), were synthesized and characterized for membrane interaction, analgesic activity and mechanism of action. Ibuprofen enhanced peptide-membrane interaction, endowing a specificity for anionic fluid bilayers. A direct correlation between anionic lipid affinity and analgesic effect was established, IbKTP-NH 2 being the most potent analgesic (from 25 μmol·kg -1). In vitro, IbKTP-NH 2 caused the biggest shift in the membrane surface charge of BBB endothelial cells, as quantified using zeta-potential dynamic light scattering. Our results suggest that IbKTP-NH 2 crosses the BBB and acts by activating both opioid dependent and independent pathways

© Molecular Pharmaceutics, 2011, vol. 8, p. 1929-1940

American Chemical Society (ACS)

Author: Ribeiro, Marta M B
Pinto, Antónia R T
Domingues, Marco M.
Serrano, Isa D.
Heras i Corominas, Montserrat
Bardají Rodríguez, Eduard
Tavares, Isaura R.
Castanho, Miguel Augusto Rico Botas
Date: 2011 October 3
Abstract: The pharmaceutical potential of natural analgesic peptides is mainly hampered by their inability to cross the blood-brain barrier, BBB. Increasing peptide-cell membrane affinity through drug design is a promising strategy to overcome this limitation. To address this challenge, we grafted ibuprofen (IBP), a nonsteroidal anti-inflammatory drug, to kyotorphin (l-Tyr-l-Arg, KTP), an analgesic neuropeptide unable to cross BBB. Two new KTP derivatives, IBP-KTP (IbKTP-OH) and IBP-KTP-amide (IbKTP-NH 2), were synthesized and characterized for membrane interaction, analgesic activity and mechanism of action. Ibuprofen enhanced peptide-membrane interaction, endowing a specificity for anionic fluid bilayers. A direct correlation between anionic lipid affinity and analgesic effect was established, IbKTP-NH 2 being the most potent analgesic (from 25 μmol·kg -1). In vitro, IbKTP-NH 2 caused the biggest shift in the membrane surface charge of BBB endothelial cells, as quantified using zeta-potential dynamic light scattering. Our results suggest that IbKTP-NH 2 crosses the BBB and acts by activating both opioid dependent and independent pathways
Format: application/pdf
ISSN: 1543-8384
Document access: http://hdl.handle.net/10256/10174
Language: eng
Publisher: American Chemical Society (ACS)
Collection: Reproducció digital del document publicat a: http://dx.doi.org/10.1021/mp2003016
Articles publicats (D-Q)
info:eu-repo/grantAgreement/EC/FP7/230654
Is part of: © Molecular Pharmaceutics, 2011, vol. 8, p. 1929-1940
Rights: Tots els drets reservats
Subject: Neuropèptids
Neuropeptides
Analgèsics
Analgesics
Ibuprofèn
Title: Chemical conjugation of the neuropeptide kyotorphin and ibuprofen enhances brain targeting and analgesia
Type: info:eu-repo/semantics/article
Repository: DUGiDocs

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