title: Chemical conjugation of the neuropeptide kyotorphin and ibuprofen enhances brain targeting and analgesia.
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.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av Professor Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Marta M B
authors.initials: MM
authors.lastname: Ribeiro
authors.forename: Antónia R T
authors.initials: AR
authors.lastname: Pinto
authors.forename: Marco M
authors.initials: MM
authors.lastname: Domingues
authors.forename: Isa
authors.initials: I
authors.lastname: Serrano
authors.forename: Montserrat
authors.initials: M
authors.lastname: Heras
authors.forename: Eduard R
authors.initials: ER
authors.lastname: Bardaji
authors.forename: Isaura
authors.initials: I
authors.lastname: Tavares
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Castanho
mesh_terms: D000700:Analgesics / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D018712:Analgesics, Non-Narcotic / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000737:chemistry; D015195:Drug Design; D004723:Endorphins / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007052:Ibuprofen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003432:Cross-Linking Reagents; D004723:Endorphins; D008051:Lipid Bilayers; C019448:kyotorphin; D007052:Ibuprofen