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Metabolic fate of lactoferricin based antimicrobial peptides: effect of truncation and incorporation of amino acid analogs on the in vitro metabolic stability

Johan Svenson, Valentijn Vergote UGent, Rasmus Karsted, Christian Burvenich UGent, John Svendsen and Bart De Spiegeleer UGent (2010) JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. 332(3). p.1032-1039
abstract
A series of promising truncated antibacterial tripeptides derived from lactoferricin has been prepared, and their in vitro metabolic stability in the main metabolic compartments, plasma, liver, kidney, stomach, duodenum, and brain, has been investigated for the first time. The potential stabilizing effect of truncation, C-terminal capping, and introduction of the bulky synthetic amino acid biphenylalanine is also investigated. The drug-like peptides displayed large differences in half-lives in the different matrixes ranging from 4.2 min in stomach and duodenum to 355.9 min in liver. Kinetic analysis of the metabolites revealed that several different degrading enzymes simultaneously target the different peptide bonds and that the out-come of the tested strategies to increase the stability is clearly enzyme-specific. Some of the metabolic enzymes even prefer the synthetic modifications incorporated over the natural counterparts. Collectively, it is shown that the necessary antibacterial pharmacophore generates compounds that are not only potent antibacterial peptides, but excellent substrates for the main degrading enzymes. All the amide bonds are thus rapidly targeted by different enzymes despite the short peptidic sequences of the tested compounds. Hence, our results illustrate that several structural changes are needed before these compounds can be considered for oral administration. Strategies to overcome such metabolic challenges are discussed.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
Lactoferricin, Metabolization, Peptides, Antimicrobial, ANTIBACTERIAL ACTIVITY, BOVINE LACTOFERRICIN, FUNCTIONAL FRAGMENTS, ADULT RATS, DERIVATIVES, IDENTIFICATION, DEGRADATION, STRATEGIES, TRYPTOPHAN, OBESTATIN
journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
J. Pharmacol. Exp. Ther.
volume
332
issue
3
pages
1032 - 1039
Web of Science type
Article
Web of Science id
000274800200038
JCR category
PHARMACOLOGY & PHARMACY
JCR impact factor
4.017 (2010)
JCR rank
40/249 (2010)
JCR quartile
1 (2010)
ISSN
0022-3565
DOI
10.1124/jpet.109.162826
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
798903
handle
http://hdl.handle.net/1854/LU-798903
date created
2009-12-04 05:22:47
date last changed
2012-11-06 10:11:42
@article{798903,
  abstract     = {A series of promising truncated antibacterial tripeptides derived from lactoferricin has been prepared, and their in vitro metabolic stability in the main metabolic compartments, plasma, liver, kidney, stomach, duodenum, and brain, has been investigated for the first time. The potential stabilizing effect of truncation, C-terminal capping, and introduction of the bulky synthetic amino acid biphenylalanine is also investigated. The drug-like peptides displayed large differences in half-lives in the different matrixes ranging from 4.2 min in stomach and duodenum to 355.9 min in liver. Kinetic analysis of the metabolites revealed that several different degrading enzymes simultaneously target the different peptide bonds and that the out-come of the tested strategies to increase the stability is clearly enzyme-specific. Some of the metabolic enzymes even prefer the synthetic modifications incorporated over the natural counterparts. Collectively, it is shown that the necessary antibacterial pharmacophore generates compounds that are not only potent antibacterial peptides, but excellent substrates for the main degrading enzymes. All the amide bonds are thus rapidly targeted by different enzymes despite the short peptidic sequences of the tested compounds. Hence, our results illustrate that several structural changes are needed before these compounds can be considered for oral administration. Strategies to overcome such metabolic challenges are discussed.},
  author       = {Svenson, Johan and Vergote, Valentijn and Karsted, Rasmus and Burvenich, Christian and Svendsen, John and De Spiegeleer, Bart},
  issn         = {0022-3565},
  journal      = {JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS},
  keyword      = {Lactoferricin,Metabolization,Peptides,Antimicrobial,ANTIBACTERIAL ACTIVITY,BOVINE LACTOFERRICIN,FUNCTIONAL FRAGMENTS,ADULT RATS,DERIVATIVES,IDENTIFICATION,DEGRADATION,STRATEGIES,TRYPTOPHAN,OBESTATIN},
  language     = {eng},
  number       = {3},
  pages        = {1032--1039},
  title        = {Metabolic fate of lactoferricin based antimicrobial peptides: effect of truncation and incorporation of amino acid analogs on the in vitro metabolic stability},
  url          = {http://dx.doi.org/10.1124/jpet.109.162826},
  volume       = {332},
  year         = {2010},
}

Chicago
Svenson, Johan, Valentijn Vergote, Rasmus Karsted, Christian Burvenich, John Svendsen, and Bart De Spiegeleer. 2010. “Metabolic Fate of Lactoferricin Based Antimicrobial Peptides: Effect of Truncation and Incorporation of Amino Acid Analogs on the in Vitro Metabolic Stability.” Journal of Pharmacology and Experimental Therapeutics 332 (3): 1032–1039.
APA
Svenson, J., Vergote, V., Karsted, R., Burvenich, C., Svendsen, J., & De Spiegeleer, B. (2010). Metabolic fate of lactoferricin based antimicrobial peptides: effect of truncation and incorporation of amino acid analogs on the in vitro metabolic stability. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 332(3), 1032–1039.
Vancouver
1.
Svenson J, Vergote V, Karsted R, Burvenich C, Svendsen J, De Spiegeleer B. Metabolic fate of lactoferricin based antimicrobial peptides: effect of truncation and incorporation of amino acid analogs on the in vitro metabolic stability. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. 2010;332(3):1032–9.
MLA
Svenson, Johan, Valentijn Vergote, Rasmus Karsted, et al. “Metabolic Fate of Lactoferricin Based Antimicrobial Peptides: Effect of Truncation and Incorporation of Amino Acid Analogs on the in Vitro Metabolic Stability.” JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 332.3 (2010): 1032–1039. Print.