MiniAp-4: A Venom-Inspired Peptidomimetic for Brain Delivery.
Drug delivery across the blood-brain barrier (BBB) is a formidable challenge for therapies targeting the central nervous system. Although BBB shuttle peptides enhance transport into the brain non-invasively, their application is partly limited by lability to proteases. The present study proposes the use of cyclic peptides derived from venoms as an affordable way to circumvent this drawback. Apamin, a neurotoxin from bee venom, was minimized by reducing its complexity, toxicity, and immunogenicity, while preserving brain targeting, active transport, and protease resistance. Among the analogues designed, the monocyclic lactam-bridged peptidomimetic MiniAp-4 was the most permeable. This molecule is capable of translocating proteins and nanoparticles in a human-cell-based BBB model. Furthermore, MiniAp-4 can efficiently deliver a cargo across the BBB into the brain parenchyma of mice.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona (Spain).
Benjamí
B
Oller-Salvia
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona (Spain).
Macarena
M
Sánchez-Navarro
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona (Spain).
Sonia
S
Ciudad
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona (Spain).
Marc
M
Guiu
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona (Spain).
Pol
P
Arranz-Gibert
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona (Spain).
Cristina
C
Garcia
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona (Spain).|ICREA (Spain).
Roger R
RR
Gomis
University of Artois, Faculté Jean Perrin, Jean Souvraz-SP 18, 62307 Lens (France).
Roméo
R
Cecchelli
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona (Spain).
Jesús
J
García
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona (Spain). ernest.giralt@irbbarcelona.org.|University of Barcelona, Department of Organic Chemistry (Spain). ernest.giralt@irbbarcelona.org.
Ernest
E
Giralt
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona (Spain). meritxell.teixido@irbbarcelona.org.
Meritxell
M
Teixidó
D000595:Amino Acid Sequence; D001030:Apamin / Q000737:chemistry*; D001812:Blood-Brain Barrier; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D057786:Peptidomimetics / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D014688:Venoms / Q000008:administration & dosage*
D057786:Peptidomimetics; D014688:Venoms; D001030:Apamin
apamin; blood-brain barrier; drug delivery; peptides