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Analytical characterization of the blood-brain barrier transport of peptides

(2012)
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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.
Keywords
dehalogenation, peptide purity, chromatography, Blood-brain barrier, Brainpeps database, peptides

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Please use this url to cite or link to this publication:

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.
@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},
}