Shuttle peptides are peptides or peptide conjugates designed to allow the transport or delivery of therapeutic payloads, such as drugs, oligonucleotides, or proteins, through cell or tissue barriers, for example, the blood-brain barrier, to their targets in cells, for instance, to targets in the nervous system.
The delivery of drugs into the brain is a significant challenge. The blood-brain barrier (BBB) prevents most drugs from reaching targets in the brain. Molecular transport vehicles or shuttles based on peptides offer new avenues of crossing the BBB. Well-designed shuttle peptides are of lower cost, have reduced immunogenicity, and are biological and chemical very versatile. Improved drugs for the central nervous system (CNS) can potentially enhance the well-being of many people suffering from neurological diseases such as brain cancer.
The BBB is a complex of tight junctions of the brain’s capillary endothelial cells. Several transport systems are part of this cell complex. For energy, the BBB supplies creatine to the brain, transported by the creatine transporter localized at the brain capillary endothelial cells.
Brain capillary endothelial cells express serotonin and norepinephrine transporters, organic anion transporter 3 (OAT3), and the amino acid transporter ASCT2.
Oller-Salvia et al., in 2016, reported a list of shuttle peptides that cross the BBB (Table 1).
Table 1: Features of some BBB shuttle peptides
|
Peptide
|
Typical sequence
|
Proposed transporter
|
Origin
|
Main cargoes
|
BBB passage evidence
|
|
Angiopep-2
|
TFFYGGSRGK RNNFKTEEY-OH
|
LRP1
|
Neurotropic endog. Protein
|
Small drugs, proteins, nanopart., and DNA/RNA
|
BBBCM
Capillary depletion
Fluorescence microscopy
TEM
Effect on glioma, epilepsy and Parkinson's mouse models
|
|
ApoB
(3371–3409)
|
SSVIDALQYK LEGTTRLTRK-
RGLKLATALS LSNKFVEGS
|
LRP2LDLR
|
Neurotropic endog. Protein
|
Proteins
|
Capillary depletion
Effect on MPS mouse model
|
|
ApoE (159–167)2
|
(LRKLRKRLL)2
|
LRP1LRP2LDLR
|
Neurotropic endog. protein
|
Proteins and nanopart.
|
BBBCM
Capillary depletion
Fluorescence microscopy
Effect on the MLD mouse model
|
|
Peptide-22
|
Ac-C(&)MPRLRGC(&)-NH2
|
LDLR
|
Phage display (receptor)
|
Nanopart.
|
BBBCM
Live fluorescence microscopy
|
|
THR
|
THRPPMWSPVWP-NH2
|
TfR1
|
Phage display (cells)
|
RNA and nanopart.
|
BBBCM
TEM
|
|
THR retro-enantio
|
pwvpswmpprht-NH2
|
TfR1
|
Phage display-derived
|
Small drugs and nanopart.
|
BBBCM
Live fluorescence microscopy
|
|
CRT
|
C(&)RTIGPSVC(&)
|
TfR1
|
Phage display (mice)
|
Virus
|
Capillary depletion
|
|
Leptin30
|
YQQILTSMPS RNVIQISND-
LENLRDLLHV L
|
Leptin receptors
|
Neurotropic endog. protein
|
DNA
|
Capillary depletion
|
|
RVG29
|
YTIWMPENPR PGTPCDIFT-
NSRGKRASNG-OH
|
nAchR
|
Neurotropic exog. protein
|
Nanopart. and RNA/DNA
|
Capillary depletion
BBBCM
Effect in viral encephalitis and mouse models of Parkinson's disease
|
|
DCDX
|
GreirtGraerwsekf-OH
|
nAchR
|
Neurotoxin-derived
|
Nanopart.
|
BBBCM
Effect on glioblastoma
|
|
Apamin
|
C(&1)NC(&2)KAPETALC(&1)-
AR-RC(&2)QQH-NH2
|
KCa channel?
|
Neurotoxin
|
Proteins and nanopart.
|
BBBCM
|
|
MiniAp-4
|
[Dap](&)KAPETALD(&)
|
KCa channel?
|
Neurotoxin-derived
|
Small drugs, proteins and nanopart.
|
Human BBBCM
Fluorescence microscopy
|
|
GSH
|
γ-l-glutamyl-CG-OH
|
GSH transporter
|
Endog. peptide
|
Nanopart.
|
Intracerebral microdialysis
Effect on glioma and MS mouse models
|
|
G23
|
HLNILSTLWKYRC
|
GM1
|
Phage display (receptor)
|
Nanopart.
|
BBBCM
Fluorescence microscopy
|
|
g7
|
GFtGFLS(O-β-Glc)-NH2
|
Unknown receptor
|
Endog. peptide-derived
|
Nanopart.
|
Fluorescence microscopy
TEM
|
|
TGN
|
TGNYKALHPHNG
|
Unknown receptor
|
Phage display (in vivo)
|
Nanopart.
|
Fluorescence microscopy
Effect on glioma and AD mouse models
|
|
TAT (47–57)
|
YGRKKRRQRRR-NH2
|
AMT
|
Exog. protein
|
Proteins and nanopart.
|
BBBCM
Capillary depletion
Fluorescence microscopy
TEM
|
|
SynB1
|
RGGRLSYSRR RFSTSTGR
|
AMT
|
Toxin
|
Small drugs
|
Brain perfusion
Capillary depletion
|
|
Diketopiperazines
|
&(N-MePhe)–(N-MePhe) Diketo-piperazines
|
Passive diffusion
|
Design (+serendipity)
|
Small drugs
|
PAMPA
BBBCM
|
|
PhPro
|
(Phenylproline)4-NH2
|
Passive diffusion
|
Design
|
Small drug
|
PAMPA
|
|
“BBB passage evidence” includes the main strategies used to assess the presence of the compound targeted by the BBB-shuttle in the brain parenchyma or the effects derived from it. These approaches do not provide information about brain selectivity and do not prove that the whole cargo-shuttle construct crosses the BBB.
Abbreviations: Endog.: endogenous; Exog.: exogenous; nanopart.: nanoparticles; BBBCM: a cell-based BBB model; MPS: mucopolysaccharidosis; MLD: metachromatic leukodystrophy; AD: Alzheimer's disease. Nomenclature for cyclic peptides (&) is adapted to the 3-letter amino acid code from the one described by Spengler et al. [Dap] stands for diaminopropionic acid. Only selected references relevant to the study of these peptides as BBB-shuttle. (Source: Oller-Salvia et al. 2016)
|
Reference
Jiang T, Olson ES, Nguyen QT, Roy M, Jennings PA, Tsien RY. Tumor imaging by means of proteolytic activation of cell-penetrating peptides. Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17867-72. [PMC]
Ohtsuki S. New aspects of the blood-brain barrier transporters; its physiological roles in the central nervous system. Biol Pharm Bull. 2004 Oct;27(10):1489-96. [pdf]
Oller-Salvia, Benjamí and Sánchez-Navarro, Macarena and Giralt, Ernest and Teixidó, Meritxell. Blood–brain barrier shuttle peptides: an emerging paradigm for brain delivery, Chem. Soc. Rev., 2016, 45, 17, 4690-4707. The Royal Society of Chemistry. [RSC]
J. Spengler, J. C. Jiménez, K. Burger, E. Giralt and F. Albericio; Abbreviated nomenclature for cyclic and branched homo- and hetero-detic peptides. J. Pept. Res., 2005, 65 , 550-555. [PubMed]
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