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Brainpeps: the blood–brain barrier peptide database

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Abstract

Peptides are able to cross the blood–brain barrier (BBB) through various mechanisms, opening new diagnostic and therapeutic avenues. However, their BBB transport data are scattered in the literature over different disciplines, using different methodologies reporting different influx or efflux aspects. Therefore, a comprehensive BBB peptide database (Brainpeps) was constructed to collect the BBB data available in the literature. Brainpeps currently contains BBB transport information with positive as well as negative results. The database is a useful tool to prioritize peptide choices for evaluating different BBB responses or studying quantitative structure–property (BBB behaviour) relationships of peptides. Because a multitude of methods have been used to assess the BBB behaviour of compounds, we classified these methods and their responses. Moreover, the relationships between the different BBB transport methods have been clarified and visualized.

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Abbreviations

%ID:

Percentage injected dose

γ :

Surface tension

γ 0 :

Surface tension in pure buffer solution

ε :

Dielectric constant

λ :

Terminal rate constant

π :

Surface pressure

Г:

Surface excess concentration

Г∞ :

Limited surface excess concentration

A :

Area of the filter, membrane surface area, capillary surface area

ABC transporter:

ATP-binding cassette transporter

A D :

Surface area of the test compound at the air–water interface

A m :

Amount of test compound in brain

A s :

Cross-sectional area; surface area

ATP:

Adenosine triphosphate

AUC:

Area under the concentration curve

AUCbrain :

Area under the concentration curve in brain

AUCplasma :

Area under the concentration curve in plasma

BB:

Brain-to-plasma concentration ratio at steady-state, blood–brain equilibrium distribution

BBB:

Blood–brain barrier

BBB-PI:

Blood–brain barrier permeability index

BCRP:

Breast cancer resistance protein

BCSFB:

Blood–cerebrospinal fluid barrier

BEI:

Brain efflux index

BMEC:

Brain microvessel endothelial cells

B/P :

Brain-to-plasma concentration ratio at steady-state, blood–brain equilibrium distribution

Brainpeps:

Blood–brain barrier peptide database

BSA:

Bovine serum albumin

BUI:

Brain uptake index

BW:

Body weight

C :

Concentration of test compound

C 0 :

Initial concentration in donor chamber; minimum concentration to induce surface activity

C a, C A, C acc :

Apical (luminal) side concentration, i.e. in the acceptor chamber

Caco-2:

Human colon carcinoma cell line

Calcein-AM:

Calcein acetoxymethyl ester

CBF:

Cerebral blood flow

C br, C brain :

Brain concentration

C br,tot, C br (total):

Total brain concentration

C buffer :

Concentration in buffer

C CSF :

Concentration in the CSF

CD:

Compartmental distribution

C donor, C d, C D, C DO, C I :

Initial concentration of test compound in donor chamber

C dial :

Concentration of the dialysate

C ECF :

Concentration of test compound in brain ECF

C in :

Concentration of the perfusate; concentration in the carotid injection solution

C iv :

Concentration of intravascular marker

Cl:

Clearance

Cleff :

Efflux clearance

ClH :

Hepatic clearance

Clinf :

Uptake clearance

Clp :

Systemic clearance

ClR :

Renal clearance

ClS :

Systemic clearance

Cltest :

Clearance of the test experiment

Clup :

Initial uptake clearance

CMC:

Critical micelle concentration

CNS:

Central nervous system

CNS− :

Low brain penetrator

CNS+ :

High brain penetrator

Conc(test/ref)brain :

Concentration ratio of test and reference compound in brain

Conc(test/ref)injectate :

Concentration ratio of test and reference compound in injection solution

C org :

Concentration test compound in organic phase

C out, C dial :

Concentration of the dialysate

C p (t):

Plasma concentration at time t

C pa :

Arterial plasma concentration

C perfusion, C perf :

Concentration in the perfusion solution

C pl :

Plasma concentration

C pl,tot :

Total plasma concentration

C ref :

Concentration of the reference compound

C ref,brain :

Concentration of the reference compound in the brain

C ref,inj :

Concentration of the reference compound in the injected solutions

C s :

Concentration of the sample

C sat :

Saturated concentration at which the surface pressure collapses

CSF:

Cerebrospinal fluid

C slice :

Free drug concentration in tissue slice

C test :

Concentration of the test compound

C test,brain :

Concentration of the test compound in the brain

C test,inj :

Concentration of the test compound in the injected solutions

C tissue :

Tissue concentration of the indicator

C tot :

Total concentration

C u :

Unbound concentration

C u,brain :

Unbound concentration in brain

C u,plasma :

Unbound concentration in plasma

C wat :

Concentration test compound in aqueous phase

C wat,ion :

Concentration of ionic species of test compound in aqueous phase

C wat,neut :

Concentration of neutral species of test compound in aqueous phase

D :

Distribution coefficient; dilution factor

dQ/dt :

Transport rate of test compound

E :

Extraction of the test compound

ECF:

Extracellular fluid

ED50 :

Dose producing 50% of the maximum response

EDTA:

Ethylenediaminetetraacetic acid

ER:

Efflux ratio; entity-relationship

E ref :

Single pass extraction of the reference compound

E refp :

Extraction of the permeable marker

E refv :

Extraction of the vascular impermeable marker

E test :

Single pass extraction of the test compound

Exp.t :

Exposure time

F :

Regional flow rate

f :

Fraction of plasma exchangeable compound

FK:

Foreign key

f u :

Unbound fraction

f u,brain :

Unbound fraction in brain

f u,dil :

Diluted unbound fraction

f u,meas :

Free fraction measured

f u,plasma :

Unbound fraction in plasma

GFR:

Glomerular filtration rate

GLUT-1:

Glucose transporter 1

hAAG:

Human α1 acid glycoprotein

HPLC:

High-performance liquid chromatography

IAM:

Immobilized artificial membrane

IUPAC:

International Union of Pure and Applied Chemistry

J :

Brain uptake rate

J max :

Maximal flux

K aw :

Air–water partition coefficient

K d :

Dissociation constant

k eff :

Apparent efflux rate constant

k el :

Plasma elimination rate constant

k el :

Efflux rate constant

k i :

Unidirectional influx rate constant determined with imaging techniques

k IAM :

IAM capacity factor

K in :

Unidirectional influx rate constant

K m :

Michaelis–Menten constant

k out :

Brain elimination rate constant

K p :

Brain-to-plasma partition coefficient

K p,app :

Apparent brain-to-plasma partition coefficient

K p,brain :

Brain-to-plasma concentration ratio

K p,in :

Intrinsic plasma-to-brain partition coefficient

K p,uu :

Brain-to-plasma partition coefficient of the free compound concentration

LAT-1:

Large neutral amino acid transporter-1

Log P cyclohexane/water :

Log P value of the cyclohexane/water system

Log P oct/water :

Log P value of the 1-octanol/water system

MBUA:

Mouse brain uptake assay

MCT:

Monocarboxylic transporters

MDCK:

Madin–Darby canine kidney cells

MDR-1:

Multidrug resistance gene

MID:

Method identification

MRI:

Magnetic resonance imaging

MRP-1:

Multidrug resistance associated protein-1

N A :

Avogadro constant

N serum :

Radioactivity measured per volume serum

N tissue :

Radioactivity measured per gram tissue

OID:

Origin identification

P :

Partition coefficient; permeability coefficient

PAMPA:

Parallel artificial membrane permeation assay

P app :

Apparent permeability coefficient, determined with BMEC, co-culture, immortalized cell lines, Caco-2, MDCK and MBUA

P app (A–B):

Apparent permeability coefficient from apical to basolateral side

P app (B–A):

Apparent permeability coefficient from basolateral to apical side

P app,pampa :

Apparent permeability coefficient, determined with PAMPA

Par-2:

Brain parietal cortex area 2

PBID:

Publication identification

P c :

Intrinsic carrier-mediated permeability

\( P_{\text{c}}^{\prime } \) :

Apparent net carrier-mediated permeability

P e :

Endothelial permeability, effective PAMPA permeability

P eff :

Effective PAMPA permeability

P endoth :

Endothelial permeability coefficient, determined with BMEC culture

PEPT1:

Peptide transporter 1

PET:

Positron emission tomography

P filter :

Permeability of the filter

Pgp:

P-glycoprotein

PI:

Permeability index

PID:

Peptide IDentification

P m :

Monolayer permeability determined with BMEC

P p :

Passive diffusive permeability

PR:

Peak response

PS :

Permeability–surface area coefficient

PS e :

PS product for the endothelial cell monolayer

PS f :

PS product of the control filter

PS t :

Total PS product

P total :

Total permeability

Q :

Cerebral blood flow

\( \dot{Q} \) :

Rate of blood flow

QAR:

Quantitative autoradiography

R :

Gas constant; recovery

Rateeff :

In vitro efflux rate

RBE4:

Immortalized primary rat brain endothelial cells

R dial :

Recovery by gain

RID:

Response identification

RL:

Recovery by loss, retrodialysis

RP-HPLC:

Reversed-phase HPLC

RR:

Relative recovery

S :

Capillary surface area

SMILES:

Simplified molecular input line entry specification

SPECT:

Single photon emission tomography

SV40:

Simian vacuolating virus 40

T :

Temperature; perfusion time

t :

Time

t 0 :

Dead time

t 1/2 :

(Terminal) half-life

t 1/2eq :

Equilibration half-life

t 1/2eq,in :

Intrinsic equilibration half-life

T :

Perfusion time

TEER:

Transendothelial electrical resistance

TM-BBB:

Transfected mouse endothelial cells

t r :

Retention time of test compound

TR-BBB:

Transfected rat endothelial cells

UML:

Unified modelling language

V 0 :

Initial distribution volume; plasma distribution volume of marker

V acc, V A :

Volume of the acceptor compartment

V br, V b :

Distribution volume in brain

V D :

Volume of donor compartment; distribution volume in brain

V e :

Volume fraction of brain

V i :

Initial distribution volume; Volume of buffer film remaining around sample slice

V max :

Maximum uptake rate

V p :

Plasma distribution volume

V R :

Volume of acceptor compartment

V u,br :

Unbound brain distribution volume

V v :

Brain vascular volume

X :

Amount of test compound in acceptor compartment

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Acknowledgments

This work was supported by a PhD grant of ‘Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen)’ (73402 to S.V.D.).

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Authors and Affiliations

  1. Drug Quality and Registration (DruQuaR) Group, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, 9000, Ghent, Belgium

    Sylvia Van Dorpe, Sofie Stalmans, Evelien Wynendaele & Bart De Spiegeleer

  2. Department of Telecommunications and Information Processing, Faculty of Engineering and Architecture, Ghent University, Sint-Pietersnieuwstraat 41, 9000, Ghent, Belgium

    Antoon Bronselaer, Joachim Nielandt & Guy De Tré

  3. Department of Psychiatry and Medical Psychology, Faculty of Medicine and Health Sciences, Ghent Hospital University, De Pintelaan 185, 9000, Ghent, Belgium

    Kurt Audenaert

  4. Department of Radiotherapy and Nuclear Medicine, Faculty of Medicine and Health Sciences, Ghent Hospital University, De Pintelaan 185, 9000, Ghent, Belgium

    Christophe Van De Wiele

  5. Departments of Physiology and Medical Imaging, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium

    Christian Burvenich & Kathelijne Peremans

  6. Pennington Biomedical Research Center, BBB Group, 6400 Perkins Road, Baton Rouge, LA, 70808, USA

    Hung Hsuchou

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  1. Sylvia Van Dorpe
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  2. Antoon Bronselaer
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  7. Christophe Van De Wiele
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  9. Kathelijne Peremans
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  10. Hung Hsuchou
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  11. Guy De Tré
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  12. Bart De Spiegeleer
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Corresponding author

Correspondence to Bart De Spiegeleer.

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Van Dorpe, S., Bronselaer, A., Nielandt, J. et al. Brainpeps: the blood–brain barrier peptide database. Brain Struct Funct 217, 687–718 (2012). https://doi.org/10.1007/s00429-011-0375-0

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  • DOI: https://doi.org/10.1007/s00429-011-0375-0

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