Lipid bilayer crossing-the gate of symmetry. Water-soluble phenylproline-based blood-brain barrier shuttles

Arranz-Gibert, Pol, Guixer, Bernat, Malakoutikhah, Morteza, Muttenthaler, Markus, Guzman, Fanny, Teixido, Meritxell and Giralt, Ernest (2015) Lipid bilayer crossing-the gate of symmetry. Water-soluble phenylproline-based blood-brain barrier shuttles. Journal of the American Chemical Society, 137 23: 7357-7364. doi:10.1021/jacs.5b02050


Author Arranz-Gibert, Pol
Guixer, Bernat
Malakoutikhah, Morteza
Muttenthaler, Markus
Guzman, Fanny
Teixido, Meritxell
Giralt, Ernest
Title Lipid bilayer crossing-the gate of symmetry. Water-soluble phenylproline-based blood-brain barrier shuttles
Journal name Journal of the American Chemical Society   Check publisher's open access policy
ISSN 1520-5126
0002-7863
Publication date 2015-06-01
Year available 2015
Sub-type Article (original research)
DOI 10.1021/jacs.5b02050
Open Access Status Not yet assessed
Volume 137
Issue 23
Start page 7357
End page 7364
Total pages 8
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Abstract Drug delivery to the brain can be achieved by various means, including blood-brain barrier (BBB) disruption, neurosurgical-based approaches, and molecular design. Recently, passive diffusion BBB shuttles have been developed to transport low-molecular-weight drug candidates to the brain which would not be able to cross unaided. The low water solubility of these BBB shuttles has, however, prevented them from becoming a mainstream tool to deliver cargos across membranes. Here, we describe the design, synthesis, physicochemical characterization, and BBB-transport properties of phenylproline tetrapeptides, (PhPro)(4), an improved class of BBB shuttles that operates via passive diffusion. These PhPro-based BBB shuttles showed 3 orders of magnitude improvement in water solubility compared to the gold-standard (N-MePhe)(4), while retaining very high transport values. Transport capacity was confirmed when two therapeutically relevant cargos, nipecotic acid and L-3,4-dihydroxyphenylalanine (i.e., L-DOPA), were attached to the shuttle. Additionally, we used the unique chiral and conformationally restricted character of the (PhPro)(4) shuttle to probe its chiral interactions with the lipid bilayer of the BBB. We studied the transport properties of 16 (PhPro)(4) stereoisomers using the parallel artificial membrane permeability assay and looked at differences in secondary structure. Most stereoisomers displayed excellent transport values, yet this study also revealed pairs of enantiomers with high enantiomeric discrimination and different secondary structure, where one enantiomer maintained its high transport values While the other had significantly lower values, thereby confirming that stereochemistry plays a significant role in passive diffusion. This could open the door to the design of chiral and membrane-specific shuttles with potential applications in cell labeling and oncology.
Formatted abstract
Drug delivery to the brain can be achieved by various means, including blood-brain barrier (BBB) disruption, neurosurgical-based approaches, and molecular design. Recently, passive diffusion BBB shuttles have been developed to transport low-molecular-weight drug candidates to the brain which would not be able to cross unaided. The low water solubility of these BBB shuttles has, however, prevented them from becoming a mainstream tool to deliver cargos across membranes. Here, we describe the design, synthesis, physicochemical characterization, and BBB-transport properties of phenylproline tetrapeptides, (PhPro)4, an improved class of BBB shuttles that operates via passive diffusion. These PhPro-based BBB shuttles showed 3 orders of magnitude improvement in water solubility compared to the gold-standard (N-MePhe)4, while retaining very high transport values. Transport capacity was confirmed when two therapeutically relevant cargos, nipecotic acid and l-3,4-dihydroxyphenylalanine (i.e., l-DOPA), were attached to the shuttle. Additionally, we used the unique chiral and conformationally restricted character of the (PhPro)4 shuttle to probe its chiral interactions with the lipid bilayer of the BBB. We studied the transport properties of 16 (PhPro)4 stereoisomers using the parallel artificial membrane permeability assay and looked at differences in secondary structure. Most stereoisomers displayed excellent transport values, yet this study also revealed pairs of enantiomers with high enantiomeric discrimination and different secondary structure, where one enantiomer maintained its high transport values while the other had significantly lower values, thereby confirming that stereochemistry plays a significant role in passive diffusion. This could open the door to the design of chiral and membrane-specific shuttles with potential applications in cell labeling and oncology.
Keyword Chemistry, Multidisciplinary
Chemistry
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID Bio2013-40716-R
2014-SGR-521
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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