Ítem


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

American Chemical Society (ACS)

Autor: 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
Data: 3 octubre 2011
Resum: 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
Accés al document: http://hdl.handle.net/10256/10174
Llenguatge: eng
Editor: American Chemical Society (ACS)
Col·lecció: info:eu-repo/semantics/altIdentifier/doi/10.1021/mp2003016
info:eu-repo/semantics/altIdentifier/issn/1543-8384
info:eu-repo/grantAgreement/EC/FP7/230654/EU/Selected peptides as drug candidates directed to pain and neurodegeneration/PEP2BRAIN
Drets: Tots els drets reservats
Matèria: Neuropèptids
Neuropeptides
Analgèsics
Analgesics
Ibuprofèn
Títol: Chemical conjugation of the neuropeptide kyotorphin and ibuprofen enhances brain targeting and analgesia
Tipus: info:eu-repo/semantics/article
Repositori: DUGiDocs

Matèries

Autors