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Chemical and metabolic stability of lactoferricin-derived cationic antimicrobial tripeptides

Bart De Spiegeleer UGent, Valentijn Vergote UGent, Johan Svenson, Rasmus Karstad and Christian Burvenich UGent (2009) PBA2009USA Program and Abstract Book.
abstract
The widespread overuse and misuse of antibiotics throughout the world has led to bacterial resistance to many commercially available antibiotics. Hence, the development of novel classes of antibiotics is required to address this pressing public health problem. Cationic antimicrobial peptides (CAPs) are considered to be a promising new class of drugs against multi-resistant bacteria. While their minimum antimicrobial motif has been defined, the limited success of CAPs as viable pharmaceutical drugs so far is partially due to unresolved chemical and metabolic stability issues. In order to obtain comprehensive information regarding the metabolic fate, 4 tripeptide-CAPs with different R1 (Trp or Bip) and R2 (H or Bn) were tested in vitro by incubation in buffer, denatured plasma/organ homogenates, viable plasma and organ homogenates. A general screening procedure was used, where aliquots are withdrawn at pre-determined time points and analyzed by gradient RPHPLC-UV/PDA-ESI/MS for determination of CAP degradation kinetics and identification of the degradation metabolites. Typical HPLC time profiles are given hereafter for ARg-Bip-Arg-NH2. The results in buffer and denatured plasma/organ homogenates (controls) were indicative for the chemical analytical stability. Mass balances indicate i.a. the suitability of the methodology and allowed the construction of the kinetic scheme. Apparent first-order half-lives were calculated for each of the peptides in the different tissues, with e.g. typical plasma values ranging between 30 and 100 minutes. Based on this information, kinetic and QSPR (Quantitative Structure-Property Relationships) models are built. Such analytically derived models can then be used to suggest directions for new CAPs with improved pharmaceutical drugability characteristics.
Please use this url to cite or link to this publication:
author
organization
year
type
conference
publication status
published
subject
keyword
Antibacterial peptide, Metabolism, Lactoferrin, Lactoferricin
in
PBA2009USA Program and Abstract Book
publisher
Elsevier BV
conference name
PBA2009USA - 21st International Symposium on Pharmaceutical & Biomedical Analysis
conference location
Orlando, FL, USA
conference start
2009-10-11
conference end
2009-10-14
language
English
UGent publication?
yes
classification
C3
copyright statement
I have retained and own the full copyright for this publication
id
771860
handle
http://hdl.handle.net/1854/LU-771860
date created
2009-11-04 09:27:56
date last changed
2009-11-06 08:31:55
@inproceedings{771860,
  abstract     = {The widespread overuse and misuse of antibiotics throughout the world has led to bacterial resistance to many commercially available antibiotics. Hence, the development of novel classes of antibiotics is required to address this pressing public health problem. Cationic antimicrobial peptides (CAPs) are considered to be a promising new class of drugs against multi-resistant bacteria. While their minimum antimicrobial motif has been defined, the limited success of CAPs as viable pharmaceutical drugs so far is partially due to unresolved chemical and metabolic stability issues.
In order to obtain comprehensive information regarding the metabolic fate, 4 tripeptide-CAPs with different R1 (Trp or Bip) and R2 (H or Bn) were tested in vitro by incubation in buffer, denatured plasma/organ homogenates, viable plasma and organ homogenates. A general screening procedure was used, where aliquots are withdrawn at pre-determined time points and analyzed by gradient RPHPLC-UV/PDA-ESI/MS for determination of CAP degradation kinetics and identification of the degradation metabolites. Typical HPLC time profiles are given hereafter for ARg-Bip-Arg-NH2.
The results in buffer and denatured plasma/organ homogenates (controls) were indicative for the chemical analytical stability. Mass balances indicate i.a. the suitability of the methodology and allowed the construction of the kinetic scheme. Apparent first-order half-lives were calculated for each of the peptides in the different tissues, with e.g. typical plasma values ranging between 30 and 100 minutes.
Based on this information, kinetic and QSPR (Quantitative Structure-Property Relationships) models are built. Such analytically derived models can then be used to suggest directions for new CAPs with improved pharmaceutical drugability characteristics.},
  author       = {De Spiegeleer, Bart and Vergote, Valentijn and Svenson, Johan and Karstad, Rasmus and Burvenich, Christian},
  booktitle    = {PBA2009USA Program and Abstract Book},
  keyword      = {Antibacterial peptide,Metabolism,Lactoferrin,Lactoferricin},
  language     = {eng},
  location     = {Orlando, FL, USA},
  publisher    = {Elsevier BV},
  title        = {Chemical and metabolic stability of lactoferricin-derived cationic antimicrobial tripeptides},
  year         = {2009},
}

Chicago
De Spiegeleer, Bart, Valentijn Vergote, Johan Svenson, Rasmus Karstad, and Christian Burvenich. 2009. “Chemical and Metabolic Stability of Lactoferricin-derived Cationic Antimicrobial Tripeptides.” In PBA2009USA Program and Abstract Book. Elsevier BV.
APA
De Spiegeleer, B., Vergote, V., Svenson, J., Karstad, R., & Burvenich, C. (2009). Chemical and metabolic stability of lactoferricin-derived cationic antimicrobial tripeptides. PBA2009USA Program and Abstract Book. Presented at the PBA2009USA - 21st International Symposium on Pharmaceutical & Biomedical Analysis, Elsevier BV.
Vancouver
1.
De Spiegeleer B, Vergote V, Svenson J, Karstad R, Burvenich C. Chemical and metabolic stability of lactoferricin-derived cationic antimicrobial tripeptides. PBA2009USA Program and Abstract Book. Elsevier BV; 2009.
MLA
De Spiegeleer, Bart, Valentijn Vergote, Johan Svenson, et al. “Chemical and Metabolic Stability of Lactoferricin-derived Cationic Antimicrobial Tripeptides.” PBA2009USA Program and Abstract Book. Elsevier BV, 2009. Print.