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Ribeiro, Marta M B
Pinto, Antónia R T Domingues, Marco M. Serrano, Isa D. Heras i Corominas, Montserrat Bardajà RodrÃguez, Eduard Tavares, Isaura R. Castanho, Miguel Augusto Rico Botas |
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2011 October 3 | |
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 | |
application/pdf | |
http://hdl.handle.net/10256/10174 | |
eng | |
American Chemical Society (ACS) | |
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 |
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Tots els drets reservats | |
Neuropèptids
Neuropeptides Analgèsics Analgesics Ibuprofèn |
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Chemical conjugation of the neuropeptide kyotorphin and ibuprofen enhances brain targeting and analgesia | |
info:eu-repo/semantics/article | |
DUGiDocs |