Design, synthesis and evaluation of peptidomimetics based on substituted bicyclic 2-pyridones-targeting virulence of uropathogenic E. coli |
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| Authors: | Berg Veronica Sellstedt Magnus Hedenström Mattias Pinkner Jerome S Hultgren Scott J Almqvist Fredrik |
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| Institution: | 1. Organic Chemistry, Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden;2. Molecular Microbiology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA;1. State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China;2. Department of Food Science and Technology, School of Biotechnology, East China University of Science and Technology, Shanghai 200237, PR China;1. College of Pharmacy, Catholic University of Daegu, Gyeongbuk 712-702, Republic of Korea;2. College of Pharmacy, Kyungpook National University, Daegu 702-701, Republic of Korea;3. College of Natural Science, Kangwon National University, Kangwon 200-701, Republic of Korea;1. Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201210, China;2. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201210, China;1. Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa;2. Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa |
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| Abstract: | 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. |
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