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Analytical characterization of the blood-brain barrier transport of peptides

Sylvia Van Dorpe UGent (2012)
abstract
Several endogenous active peptides exist in the central nervous system (CNS), but the CNS drug development is hampered by the presence of the blood-brain barrier (BBB). The evaluation, modeling and understanding of the transport mechanisms at the BBB is very important for the development and optimization of potential CNS peptide drugs. Which techniques are used to quantitatively describe the BBB transport properties? Due to the multi-disciplinary complexity of the BBB research, several methodologies, each resulting in a specific parameter, are reported. Therefore, a coherent overview of the BBB-responses was described and a comprehensive database (Brainpeps®) constructed to collect the dispersed literature data. Chromatographic behavior of peptides on fused-core stationary phases? A representative peptide set was obtained via hierarchic clustering based on their structure properties. The chromatographic peptide interactions on the fused-core systems were modeled and related to the BBB influx transport. BBB transport (influx and efflux) and how can we rank the “drugability”? The BBB transport of several (opioid) peptides was quantitatively evaluated. The best performing peptide regarding its BBB drugability (i.e. high influx and metabolic stability combined with low efflux) was rationalized with a desirability approach. What is the role of proteases and deiodinases? Many biomedical experiments, such as BBB transport analysis, require iodinated peptides. Next to proteolysis and oxidation, peptides may also show dehalogenation. Further assessment of kinetics, metabolite identification and which enzyme is the responsible was described. Which impurities are found in synthesized peptides and finalized peptide drugs? Next to the presence of synthetic impurities, peptide substances or finalized drug products may be chemically unstable. The impurities may influence the biomedically activity. Therefore, the importance of regulatory specification thresholds is discussed.
Please use this url to cite or link to this publication:
author
promoter
UGent
organization
year
type
dissertation (monograph)
subject
keyword
dehalogenation, peptide purity, chromatography, Blood-brain barrier, Brainpeps database, peptides
pages
264 + annexes pages
publisher
Ghent University. Faculty of Pharmaceutical Sciences
place of publication
Ghent, Belgium
defense location
Gent : Farmaceutisch Instituut (auditorium I)
defense date
2012-02-22 18:00
ISBN
9789461970206
language
English
UGent publication?
yes
classification
D1
additional info
dissertation consists of copyrighted material
copyright statement
I have transferred the copyright for this publication to the publisher
id
2056153
handle
http://hdl.handle.net/1854/LU-2056153
date created
2012-03-01 19:33:24
date last changed
2012-06-06 12:59:04
@phdthesis{2056153,
  abstract     = {Several endogenous active peptides exist in the central nervous system (CNS), but the CNS drug development is hampered by the presence of the blood-brain barrier (BBB). The evaluation, modeling and understanding of the transport mechanisms at the BBB is very important for the development and optimization of potential CNS peptide drugs.
Which techniques are used to quantitatively describe the BBB transport properties? 
Due to the multi-disciplinary complexity of the BBB research, several methodologies, each resulting in a specific parameter, are reported. Therefore, a coherent overview of the BBB-responses was described and a comprehensive database (Brainpeps{\textregistered}) constructed to collect the dispersed literature data.
Chromatographic behavior of peptides on fused-core stationary phases? 
A representative peptide set was obtained via hierarchic clustering based on their structure properties. The chromatographic peptide interactions on the fused-core systems were modeled and related to the BBB influx transport.
BBB transport (influx and efflux) and how can we rank the {\textquotedblleft}drugability{\textquotedblright}? 
The BBB transport of several (opioid) peptides was quantitatively evaluated. The best performing peptide regarding its BBB drugability (i.e. high influx and metabolic stability combined with low efflux) was rationalized with a desirability approach.
What is the role of proteases and deiodinases?
Many biomedical experiments, such as BBB transport analysis, require iodinated peptides. Next to proteolysis and oxidation, peptides may also show dehalogenation. Further assessment of kinetics, metabolite identification and which enzyme is the responsible was described.
Which impurities are found in synthesized peptides and finalized peptide drugs? 
Next to the presence of synthetic impurities, peptide substances or finalized drug products may be chemically unstable. The impurities may influence the biomedically activity. Therefore, the importance of regulatory specification thresholds is discussed.},
  author       = {Van Dorpe, Sylvia},
  isbn         = {9789461970206},
  keyword      = {dehalogenation,peptide purity,chromatography,Blood-brain barrier,Brainpeps database,peptides},
  language     = {eng},
  pages        = {264 + annexes},
  publisher    = {Ghent University. Faculty of Pharmaceutical Sciences},
  school       = {Ghent University},
  title        = {Analytical characterization of the blood-brain barrier transport of peptides},
  year         = {2012},
}

Chicago
Van Dorpe, Sylvia. 2012. “Analytical Characterization of the Blood-brain Barrier Transport of Peptides”. Ghent, Belgium: Ghent University. Faculty of Pharmaceutical Sciences.
APA
Van Dorpe, S. (2012). Analytical characterization of the blood-brain barrier transport of peptides. Ghent University. Faculty of Pharmaceutical Sciences, Ghent, Belgium.
Vancouver
1.
Van Dorpe S. Analytical characterization of the blood-brain barrier transport of peptides. [Ghent, Belgium]: Ghent University. Faculty of Pharmaceutical Sciences; 2012.
MLA
Van Dorpe, Sylvia. “Analytical Characterization of the Blood-brain Barrier Transport of Peptides.” 2012 : n. pag. Print.