Molecular determinants for brain targeting by peptides: a meta-analysis approach with experimental validation

Blood-brain barrier (BBB) peptide-shuttles (BBBpS) are able to translocate the BBB and reach the brain. Despite the importance of brain targeting in pharmacology, BBBpS are poorly characterized. Currently, their development relies on the empiric assumption that cell-penetrating peptides (CPPs), with...

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Bibliographic Details
Published in:Fluids and barriers of the CNS 2024-05, Vol.21 (1), p.45-45, Article 45
Main Authors: Cavaco, Marco, Fraga, Patrícia, Valle, Javier, Silva, Ruben D M, Gano, Lurdes, Correia, João D G, Andreu, David, Castanho, Miguel A R B, Neves, Vera
Format: Article
Language:English
Subjects:
Analysis
Animals
Biodistribution
Blood-brain barrier
Blood-Brain Barrier - metabolism
Blood–brain barrier (BBB)
Blood–brain barrier peptide shuttles (BBBpS)
Brain - metabolism
Brain delivery
Candidates
Cell-penetrating peptides (CPPs)
Cell-Penetrating Peptides - metabolism
Drug Delivery Systems - methods
Ethylenediaminetetraacetic acid
Humans
Hydrophobicity
Keywords
Lipid membranes
Nanoparticles
Nervous system diseases
Neurological disorders
Peptides
Physicochemical properties
Resins
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Summary:Blood-brain barrier (BBB) peptide-shuttles (BBBpS) are able to translocate the BBB and reach the brain. Despite the importance of brain targeting in pharmacology, BBBpS are poorly characterized. Currently, their development relies on the empiric assumption that cell-penetrating peptides (CPPs), with proven ability to traverse lipid membranes, will likewise behave as a BBBpS. The relationship between CPPs/BBBpS remains elusive and, to the best of our knowledge, has not hitherto been subject to thorough experimental scrutiny. In this work, we have identified/quantified the main physicochemical properties of BBBpS and then searched for CPPs with these properties, hence potential BBBpS. The specific features found for BBBpS are: (i) small size, (ii) none or few aromatic residues, (iii) hydrophobic, and (iv) slight cationic nature. Then, we selected the 10 scoring best in an ordinary least squares analysis, and tested them in vitro and in vivo. Overall, we identified the molecular determinants for brain targeting by peptides, devised a methodology that can be used to assist in the design of peptides with potential brain penetration from amino acid residue sequences, and found four new BBBpS within the CPP library.
ISSN:2045-8118
2045-8118
DOI:10.1186/s12987-024-00545-5