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Targeting the S1 and S3 subsite of trypsin with unnatural cationic amino acids generates antimicrobial peptides with potential for oral administration

Rasmus Karstad, Geir Isaksen, Evelien Wynendaele UGent, Yngve Guttormsen, Bart De Spiegeleer UGent, Bjorn-Olav Brandsdal, John Sigurd Svendsen and Johan Svenson (2012) JOURNAL OF MEDICINAL CHEMISTRY. 55(14). p.6294-6305
abstract
This study investigates how the S1 and S3 site of trypsin can be challenged with cationic amino acid analogues to yield active antimicrobial peptides with stability toward tryptic degradation. It is shown that unnatural analogues can be incorporated to generate stable peptides with maintained bioactivity to allow for a potential oral uptake. Selected peptides were studied using isothermal calorimetry and computational methods. Both stable and unstable peptides were found to bind stoichiometrically to trypsin with dissociation constants ranging 2-60 mu M, suggesting several different binding modes. The stability of selected peptides was analyzed in whole organ extracts and the incorporation of homoarginine and 2-amino-(3-guanidino)propanoic acid resulted in a 14- and 50-fold increase in duodenal stability. In addition, a 40- and 70-fold increase in stomach stability is also reported. Overall, these results illustrate how the incorporation of cationic side chains can be employed to generate bioactive peptides with significant systemic stability.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
DEGRADATION, SIDE-CHAINS, ANALOGS, PROTEASE, SPECIFICITY, ANTIBACTERIAL PEPTIDES, TRYPTIC DIGESTION, SUBSTRATE-BINDING, STRATEGIES, VITRO METABOLIC STABILITY
journal title
JOURNAL OF MEDICINAL CHEMISTRY
J. Med. Chem.
volume
55
issue
14
pages
6294 - 6305
Web of Science type
Article
Web of Science id
000306764600004
JCR category
CHEMISTRY, MEDICINAL
JCR impact factor
5.614 (2012)
JCR rank
3/59 (2012)
JCR quartile
1 (2012)
ISSN
0022-2623
DOI
10.1021/jm3002058
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
3033922
handle
http://hdl.handle.net/1854/LU-3033922
date created
2012-10-25 08:15:05
date last changed
2012-10-25 10:57:39
@article{3033922,
  abstract     = {This study investigates how the S1 and S3 site of trypsin can be challenged with cationic amino acid analogues to yield active antimicrobial peptides with stability toward tryptic degradation. It is shown that unnatural analogues can be incorporated to generate stable peptides with maintained bioactivity to allow for a potential oral uptake. Selected peptides were studied using isothermal calorimetry and computational methods. Both stable and unstable peptides were found to bind stoichiometrically to trypsin with dissociation constants ranging 2-60 mu M, suggesting several different binding modes. The stability of selected peptides was analyzed in whole organ extracts and the incorporation of homoarginine and 2-amino-(3-guanidino)propanoic acid resulted in a 14- and 50-fold increase in duodenal stability. In addition, a 40- and 70-fold increase in stomach stability is also reported. Overall, these results illustrate how the incorporation of cationic side chains can be employed to generate bioactive peptides with significant systemic stability.},
  author       = {Karstad, Rasmus and Isaksen, Geir and Wynendaele, Evelien and Guttormsen, Yngve and De Spiegeleer, Bart and Brandsdal, Bjorn-Olav and Svendsen, John Sigurd and Svenson, Johan},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  keyword      = {DEGRADATION,SIDE-CHAINS,ANALOGS,PROTEASE,SPECIFICITY,ANTIBACTERIAL PEPTIDES,TRYPTIC DIGESTION,SUBSTRATE-BINDING,STRATEGIES,VITRO METABOLIC STABILITY},
  language     = {eng},
  number       = {14},
  pages        = {6294--6305},
  title        = {Targeting the S1 and S3 subsite of trypsin with unnatural cationic amino acids generates antimicrobial peptides with potential for oral administration},
  url          = {http://dx.doi.org/10.1021/jm3002058},
  volume       = {55},
  year         = {2012},
}

Chicago
Karstad, Rasmus, Geir Isaksen, Evelien Wynendaele, Yngve Guttormsen, Bart De Spiegeleer, Bjorn-Olav Brandsdal, John Sigurd Svendsen, and Johan Svenson. 2012. “Targeting the S1 and S3 Subsite of Trypsin with Unnatural Cationic Amino Acids Generates Antimicrobial Peptides with Potential for Oral Administration.” Journal of Medicinal Chemistry 55 (14): 6294–6305.
APA
Karstad, R., Isaksen, G., Wynendaele, E., Guttormsen, Y., De Spiegeleer, B., Brandsdal, B.-O., Svendsen, J. S., et al. (2012). Targeting the S1 and S3 subsite of trypsin with unnatural cationic amino acids generates antimicrobial peptides with potential for oral administration. JOURNAL OF MEDICINAL CHEMISTRY, 55(14), 6294–6305.
Vancouver
1.
Karstad R, Isaksen G, Wynendaele E, Guttormsen Y, De Spiegeleer B, Brandsdal B-O, et al. Targeting the S1 and S3 subsite of trypsin with unnatural cationic amino acids generates antimicrobial peptides with potential for oral administration. JOURNAL OF MEDICINAL CHEMISTRY. 2012;55(14):6294–305.
MLA
Karstad, Rasmus, Geir Isaksen, Evelien Wynendaele, et al. “Targeting the S1 and S3 Subsite of Trypsin with Unnatural Cationic Amino Acids Generates Antimicrobial Peptides with Potential for Oral Administration.” JOURNAL OF MEDICINAL CHEMISTRY 55.14 (2012): 6294–6305. Print.