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Design, synthesis and evaluation of peptidomimetics based on substituted bicyclic 2-pyridones-targeting virulence of uropathogenic E. coli
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
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2006 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, nr 22, s. 7563-7581Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Substituted bicyclic 2-pyridones, termed pilicides, are dipeptide mimetics that prevent pilus assembly in uropathogenic Escherichia coli. Here, we apply rational design to produce four classes of extended peptidomimetics based on two bioactive 2-pyridones. The key intermediate in the synthesis was an amino-functionalised 2-pyridone scaffold, which could be obtained via a mild and selective nitration and subsequent reduction. Procedures were then developed to further derivatize this amino-substituted core and a total of 24 extended peptidomimetics were synthesised and evaluated for chaperone affinity and in vivo antivirulence activity in P pili producing E. coli. Enhanced affinities for the target protein were observed within the generated set of compounds, while the ability to prevent pilus assembly in vivo was significantly decreased compared to the parent lead compounds. The results suggest that the limited in vivo potencies of the analogues are either uptake/distribution related or due to loss in binding specificity.

Ort, förlag, år, upplaga, sidor
Oxford: Pergamon Press , 2006. Vol. 14, nr 22, s. 7563-7581
Nyckelord [en]
Bicyclo Compounds; Heterocyclic/*chemical synthesis/chemistry/*pharmacology, Biomimetics, Crystallography; X-Ray, Drug Design, Escherichia coli/*drug effects/*pathogenicity, Magnetic Resonance Spectroscopy, Molecular Chaperones/chemistry/metabolism, Molecular Structure, Peptides/*chemistry, Pyridones/*chemistry, Structure-Activity Relationship, Urinary Tract/microbiology
Identifikatorer
URN: urn:nbn:se:umu:diva-12343DOI: 10.1016/j.bmc.2006.07.017PubMedID: 16904898OAI: oai:DiVA.org:umu-12343DiVA, id: diva2:152014
Tillgänglig från: 2008-04-10 Skapad: 2008-04-10 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. Peptidomimetics based on ring-fused 2-pyridones: probing pilicide function in uropathogenic E. coli and identification of Aβ-peptide aggregation inhibitors
Öppna denna publikation i ny flik eller fönster >>Peptidomimetics based on ring-fused 2-pyridones: probing pilicide function in uropathogenic E. coli and identification of Aβ-peptide aggregation inhibitors
2006 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

This thesis describes the synthesis and biological evaluation of highly substituted, ring-fused 2-pyridones. The utility of the bicyclic 2-pyridones to gain fundamental insights into the disease processes of bacterial infections and Alzheimer’s disease has been investigated.

The 2-pyridones have mainly been studied as a new class of anti-infective agents termed pilicides. The function of the pilicides has been explored using uropathogenic E. coli (UPEC) as a prototype pathogen and urinary tract infection as a model disease. The pilicides target the infectious ability of UPEC by inhibiting key proteins (chaperones) in the so-called chaperone-usher pathway, thus preventing the assembly of bacterial surface organelles (pili/fimbriae).

Synthetic pathways to aminomethylate the 2-pyridones have been developed in order to increase their aqueous solubility while retaining biological activity. Also, the importance of a carboxylic acid has been demonstrated in studies with various carboxylate derivatives and by bioisosteric replacement. Moreover, synthetic procedures to extend the backbone of the rigid, dipeptide-mimicking 2-pyridones have been established. This rendered peptidomimetic building blocks and structures that alongside their potential use as pilicides are of more general interest in peptidomimetic-related research.

The potential pilicides have been screened for chaperone affinity using relaxation-edited 1H-NMR spectroscopy. In addition, their ability to inhibit pilus biogenesis in E. coli has been demonstrated by assays of hemagglutination, biofilm formation and attachment to bladder cells, as well as with electron and atomic force microscopy. Moreover, it has been confirmed that pilicides regulate the expression of pili without affecting the biofunctional properties of the pilus rod. This was verified by measurements of individual P pili, on living bacteria, using force measuring optical tweezers. The pilicide binding site was investigated using NMR spectroscopy and X-ray crystallography of a pilicide-chaperone complex. Based on the results obtained, a mechanism whereby the pilicides may inhibit pilus assembly was proposed, which was subsequently experimentally supported by surface plasmon resonance assays and genetic analysis.

Finally, based on the generic 2-pyridone scaffold, a new collection of substituted compounds has been synthesized and validated as inhibitors of Amyloid β (Aβ)-peptide aggregation, which has been suggested to be involved in Alzheimer’s disease.

Ort, förlag, år, upplaga, sidor
Umeå: Kemi, 2006. s. 101
Nyckelord
2-pyridone, peptidomimetic, antibacterial, pili, Escherichia coli, virulence, amyloid, Alzheimer’s.
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:umu:diva-909 (URN)91-7264-157-6 (ISBN)
Disputation
2006-11-24, KB3B1, KBC, Linneaus väg 7, 901 87 Umeå, Umeå, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2006-11-02 Skapad: 2006-11-02 Senast uppdaterad: 2011-04-21Bibliografiskt granskad

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Sellstedt, MagnusHedenström, MattiasAlmqvist, Fredrik

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