umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Multivariate design, synthesis, and biological evaluation of peptide inhibitors of FimC/FimH protein-protein interactions in uropathogenic Escherichia coli
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Show others and affiliations
2005 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 48, no 4, 935-945 p.Article in journal (Refereed) Published
Abstract [en]

A peptide library targeting protein-protein interactions crucial for pilus assembly in Gram negative bacteria has been designed using statistical molecular design. A nonamer peptide scaffold was used, with seven positions being varied. The selection was performed in the building block space, and previously known structure-activity data were included in the design procedure. This resulted in a heavily reduced library consisting of 32 peptides which was prepared by solid-phase synthesis. The ability of the peptides to inhibit the protein-protein interaction between the periplasmic chaperone FimC and the pilus adhesin FimH was then determined in an ELISA. Novel peptides with the capability to inhibit the FimC/FimH protein(-)protein interaction to the same extent as the native FimC peptides were discovered. Multivariate QSAR studies of the response in the ELISA gave valuable information on the properties of amino acids which were preferred at the seven positions in the nonamer scaffold. This information can be used in attempts to develop optimized peptides and peptidomimetics that inhibit pilus assembly in pathogenic bacteria.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2005. Vol. 48, no 4, 935-945 p.
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-13553DOI: 10.1021/jm040818lOAI: oai:DiVA.org:umu-13553DiVA: diva2:153224
Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2012-06-15Bibliographically approved
In thesis
1. Antiadhesive agents targeting uropathogenic Escherichia coli: Multivariate studies of protein-protein and protein-carbohydrate interactions
Open this publication in new window or tab >>Antiadhesive agents targeting uropathogenic Escherichia coli: Multivariate studies of protein-protein and protein-carbohydrate interactions
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Antiadhesiva substanser riktade mot uropatogena Escherichia coli : Multivariata studier av protein-protein och protein-kolhydrat interaktioner
Abstract [en]

This thesis describes studies directed towards development of novel antiadhesive agents, with particular emphasis on compounds that prevent attachment of bacteria to a host-cell. Three different proteins involved in the assembly or function of adhesive pili in uropathogenic Escherichia coli have been targeted either by rational structure based design or statistical molecular methods.

A library of substituted galabiose (Galα1-4Gal) derivatives was screened for binding to the E. coli adhesin PapG in an assay based on surface plasmon resonance, and for inhibition of Streptococcus suis adhesins PN and PO in a hemagglutination assay. The results were used to generate QSAR models which had good predictive powers and provided further insight in the structural requirements needed for high affinity binding.

2-pyridones and amino acid derivatives were modelled into the binding site of chaperones involved in pilus assembly in E. coli and a heuristic method, VALIDATE, was used for affinity prediction. The affinity of the compounds for the chaperones PapD and FimC were assessed in assays based on surface plasmon resonance and relaxation-edited NMR spectroscopy. Their ability to disrupt chaperone/subunit complexes was investigated in vitro through a FPLC assay and their capacity to inhibit pilus formation in vivo was determined via hemagglutination and confirmed with atomic force microscopy.

Statistical molecular design was used to design a diverse peptide library targeting pili subunits, and an ELISA was developed to investigate the ability of the peptides to inhibit chaperone/subunit complexation. The resulting QSAR model provided extensive information regarding binding of the peptides to the subunits. Because the peptides were suggested to bind in an extended β-strand formation, β-strand mimetics consisting of oligomeric enaminones were designed. Finally, new methods to synthesize enaminone building blocks were developed using microwave assisted chemistry.

The projects described have generated compounds that besides their value as leads for developing novel antibacterial agents, also constitute new chemical tools to study the mechanisms underlying bacterial virulence.

Place, publisher, year, edition, pages
Umeå: Kemi, 2004. 92 p.
Keyword
Organic chemistry, Antibacterial, pili, antiadhesive agents, structure based design, statistical molecular design, 2-pyridone, amino acid derivative, galabiose, enaminone, SPR, ELISA, QSAR, Organisk kemi
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-314 (URN)91-7305-731-2 (ISBN)
Public defence
2004-10-01, KB3B1, KBC, Umeå Universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2004-09-13 Created: 2004-09-13 Last updated: 2012-06-15Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Authority records BETA

Larsson, AndreasAlmqvist, FredrikKihlberg, JanLinusson, Anna

Search in DiVA

By author/editor
Larsson, AndreasJohansson, Susanne M. C.Almqvist, FredrikKihlberg, JanLinusson, Anna
By organisation
Department of Chemistry
In the same journal
Journal of Medicinal Chemistry
Chemical Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 164 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf