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  • 1.
    Andersson, C. David
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Forsgren, Nina
    Swedish Defense Research Agency, CBRN Defense and Security, Umeå.
    Akfur, Christine
    Swedish Defense Research Agency, CBRN Defense and Security, Umeå.
    Allgardsson, Anders
    Swedish Defense Research Agency, CBRN Defense and Security, Umeå.
    Berg, Lotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Engdahl, Cecilia
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Swedish Defense Research Agency, CBRN Defense and Security, Umeå.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Laboratories for Chemical Biology Umeå (LCBU), Umeå University,.
    Ekström, Fredrik
    Swedish Defense Research Agency, CBRN Defense and Security, Umeå.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Divergent Structure-Activity Relationships of Structurally Similar Acetylcholinesterase Inhibitors2013In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 19, p. 7615-7624Article in journal (Refereed)
    Abstract [en]

    The molecular interactions between the enzyme acetylcholinesterase (AChE) and two compound classes consisting of N-[2-(diethylamino)ethyl]benzenesulfonamides and N-[2-(diethylamino)ethyl]benzenemethanesulfonamides have been investigated using organic synthesis, enzymatic assays, X-ray crystallography, and thermodynamic profiling. The inhibitors' aromatic properties were varied to establish structure activity relationships (SAR) between the inhibitors and the peripheral anionic site (PAS) of AChE. The two structurally similar compound classes proved to have distinctly divergent SARs in terms of their inhibition capacity of AChE. Eight X-ray structures revealed that the two sets have different conformations in PAS. Furthermore, thermodynamic profiles of the binding between compounds and AChE revealed class-dependent differences of the entropy/enthalpy contributions to the free energy of binding. Further development of the entropy-favored compound class resulted in the synthesis of the most potent inhibitor and an extension beyond the established SARs. The divergent SARs will be utilized to develop reversible inhibitors of AChE into reactivators of nerve agent-inhibited AChE.

  • 2.
    Andersson, C. David
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hillgren, J. Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Chemistry and Molecular Biology - Medicinal Chemistry, University of Gothenburg.
    Lindgren, Cecilia
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Laboratories for Chemical Biology Umeå, Umeå University.
    Akfur, Christine
    Berg, Lotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ekström, Fredrik
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Benefits of statistical molecular design, covariance analysis, and reference models in QSAR: a case study on acetylcholinesterase2015In: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 29, no 3, p. 199-215Article in journal (Refereed)
    Abstract [en]

    Scientific disciplines such as medicinal- and environmental chemistry, pharmacology, and toxicology deal with the questions related to the effects small organic compounds exhort on biological targets and the compounds' physicochemical properties responsible for these effects. A common strategy in this endeavor is to establish structure-activity relationships (SARs). The aim of this work was to illustrate benefits of performing a statistical molecular design (SMD) and proper statistical analysis of the molecules' properties before SAR and quantitative structure-activity relationship (QSAR) analysis. Our SMD followed by synthesis yielded a set of inhibitors of the enzyme acetylcholinesterase (AChE) that had very few inherent dependencies between the substructures in the molecules. If such dependencies exist, they cause severe errors in SAR interpretation and predictions by QSAR-models, and leave a set of molecules less suitable for future decision-making. In our study, SAR- and QSAR models could show which molecular sub-structures and physicochemical features that were advantageous for the AChE inhibition. Finally, the QSAR model was used for the prediction of the inhibition of AChE by an external prediction set of molecules. The accuracy of these predictions was asserted by statistical significance tests and by comparisons to simple but relevant reference models.

  • 3.
    Berg, Lotta
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Niemiec, Moritz S.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ekström, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, European CBRNE Center.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Similar but Different: Thermodynamic and Structural Characterization of a Pair of Enantiomers Binding to Acetylcholinesterase2012In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 51, no 51, p. 12716-12720Article in journal (Refereed)
    Abstract [en]

    Take a closer look: Unexpectedly, a pair of enantiomeric ligands proved to have similar binding affinities for acetylcholinesterase. Further studies indicated that the enantiomers exhibit different thermodynamic profiles. Analyses of the noncovalent interactions in the protein-ligand complexes revealed that these differences are partly due to nonclassical hydrogen bonds between the ligands and aromatic side chains of the protein.

  • 4.
    Caraballo, Remi
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Larsson, Mikael
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Nilsson, Stefan K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tran, Nam Phuong Nguyen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kindahl, Tomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Richard
    Uppsala, Sweden.
    Saar, Valeria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Artursson, Per
    Uppsala, Sweden.
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Enquist, Per-Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo2015In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 103, p. 191-209Article in journal (Refereed)
    Abstract [en]

    The risk of cardiovascular events increases in individuals with elevated plasma triglyceride (TG) levels, therefore advocating the need for efficient TG-lowering drugs. In the blood circulation, TG levels are regulated by lipoprotein lipase (LPL), an unstable enzyme that is only active as a non-covalently associated homodimer. We recently reported on a N-phenylphthalimide derivative (1) that stabilizes LPL in vitro, and moderately lowers triglycerides in vivo (Biochem. Biophys. Res. Common. 2014, 450, 1063). Herein, we establish structure activity relationships of 51 N-phenylphthalimide analogs of the screening hit 1. In vitro evaluation highlighted that modifications on the phthalimide moiety were not tolerated and that lipophilic substituents on the central phenyl ring were functionally essential. The substitution pattern on the central phenyl ring also proved important to stabilize LPL However, in vitro testing demonstrated rapid degradation of the phthalimide fragment in plasma which was addressed by replacing the phthalimide scaffold with other heterocyclic fragments. The in vitro potency was retained or improved and substance 80 proved stable in plasma and efficiently lowered plasma TGs in vivo. 2015 The Authors. Published by Elsevier Masson SAS.

  • 5.
    Caraballo, Rémi
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Saleeb, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Bauer, Johannes
    Interfaculty Institute of Biochemistry, University of Tübingen, Germany.
    Liaci, Antonio-Manuel
    Interfaculty Institute of Biochemistry, University of Tübingen, Germany.
    Chandra, Naresh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Storm, Rickard J
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Stehle, Thilo
    Interfaculty Institute of Biochemistry, University of Tübingen, Germany ; Department of Pediatrics, Vanderbilt University School of Medicine, USA.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Triazole linker-based trivalent sialic acid inhibitors of adenovirus type 37 infection of human corneal epithelial cells2015In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 13, no 35, p. 9194-9205Article in journal (Refereed)
    Abstract [en]

    Adenovirus type 37 (Ad37) is one of the principal agents responsible for epidemic keratoconjunctivitis (EKC), a severe ocular infection that remains without any available treatment. Recently, a trivalent sialic acid derivative (ME0322, Angew. Chem. Int. Ed., 2011, 50, 6519) was shown to function as a highly potent inhibitor of Ad37, efficiently preventing the attachment of the virion to the host cells and subsequent infection. Here, new trivalent sialic acid derivatives were designed, synthesized and their inhibitory properties against Ad37 infection of the human corneal epithelial cells were investigated. In comparison to ME0322, the best compound (17a) was found to be over three orders of magnitude more potent in a cell-attachment assay (IC50 = 1.4 nM) and about 140 times more potent in a cell-infection assay (IC50 = 2.9nM). X-ray crystallographic analysis demonstrated a trivalent binding mode of all compounds to the Ad37 fiber knob. For the most potent compound ophthalmic toxicity in rabbits was investigated and it was concluded that repeated eye administration did not cause any adverse effects.

  • 6.
    Johansson, Susanne
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nilsson, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Kihlberg, Jan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Design, synthesis and evaluation of N-acyl modified sialic acids as inhibitors of EKC-causing adenovirusesManuscript (preprint) (Other academic)
  • 7.
    Johansson, Susanne
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nilsson, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Guilligay, Delphine
    Crepin, Thibaut
    Cusack, Stephen
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Design, synthesis, and evaluation of N-acyl modified sialic acids as inhibitors of adenoviruses causing epidemic keratoconjunctivitis2009In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 52, no 12, p. 3666-3678Article in journal (Refereed)
    Abstract [en]

    The adenovirus serotype Ad37 binds to and infects human corneal epithelial (HCE) cells through attachment to cellular glycoproteins carrying terminal sialic acids. By use of the crystallographic structure of the sialic acid-interacting domain of the Ad37 fiber protein in complex with sialyllactose, a set of N-acyl modified sialic acids were designed to improve binding affinity through increased hydrophobic interactions. These N-acyl modified sialic acids and their corresponding multivalent human serum albumin (HSA) conjugates were synthesized and tested in Ad37 cell binding and cell infectivity assays. Compounds bearing small substituents were as effective inhibitors as sialic acid. X-ray crystallography and overlays with the Ad37-sialyllactose complex showed that the N-acyl modified sialic acids were positioned in the same orientation as sialic acid. Their multivalent counterparts achieved a strong multivalency effect and were more effective to prevent infection than the monomers. Unfortunately, they were less active as inhibitors than multivalent sialic acid.

  • 8.
    Lindgren, Cecilia
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Forsgren, Nina
    Swedish Defence Research Agency, CBRN Defence and Security.
    Akfur, Christine
    Swedish Defence Research Agency, CBRN Defence and Security.
    Berg, Lotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hillgren, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Richard
    Worek, Franz
    Ekström, Fredrik
    Swedish Defence Research Agency, CBRN Defence and Security.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Design of Reactive Drugs: Structure and Mechanism of Novel Nerve Agent AntidotesManuscript (preprint) (Other academic)
  • 9.
    Pudelko, Maciej
    et al.
    Umeå University, Faculty of Science and Technology, Chemistry.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Chemistry.
    Synthesis and application of N-[1-(4-(4-fluorophenyl)-2,6-dioxocyclohexylidene)ethyl] (Fde)-protected amino acids for optimization of solid-phase peptide synthesis using gel-phase (19)F NMR spectroscopy.2009In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 15, no 4, p. 264-71Article in journal (Refereed)
    Abstract [en]

    N-[1-(4-(4-fluorophenyl)-2,6-dioxocyclohexylidene)ethyl] (Fde) protected amino acids have been prepared and applied in solid-phase peptide synthesis monitored by gel-phase (19)F NMR spectroscopy. The Fde protective group could be cleaved with 2% hydrazine or 5% hydroxylamine solution in DMF as determined with gel-phase (19)F NMR spectroscopy. The dipeptide Ac-L-Val-L-Val-NH(2) 12 was constructed using Fde-L-Val-OH and no noticeable racemization took place during the amino acid coupling with N,N'-diisopropylcarbodiimide and 1-hydroxy-7-azabenzotriazole or Fde deblocking. To extend the scope of Fde protection, the hydrophobic nonapeptide LLLLTVLTV from the signal sequence of mucin MUC1 was successfully prepared using Fde-L-Leu-OH at diagnostic positions. Copyright (c) 2009 European Peptide Society and John Wiley & Sons, Ltd.

  • 10. Rodriguez-Furlan, Cecilia
    et al.
    Domozych, David
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Chemical Biology Consortium Sweden, Umeå, Sweden.
    Enquist, Per-Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Chemical Biology Consortium Sweden, Umeå, Sweden.
    Li, Xiaohui
    Zhang, Chunhua
    Schenk, Rolf
    Winbigler, Holly Saulsbery
    Jackson, William
    Raikhel, Natasha V.
    Hicks, Glenn R.
    Interaction between VPS35 and RABG3f is necessary as a checkpoint to control fusion of late compartments with the vacuole2019In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 42, p. 21291-21301Article in journal (Refereed)
    Abstract [en]

    Vacuoles are essential organelles in plants, playing crucial roles, such as cellular material degradation, ion and metabolite storage, and turgor maintenance. Vacuoles receive material via the endocytic, secretory, and autophagic pathways. Membrane fusion is the last step during which prevacuolar compartments (PVCs) and autophagosomes fuse with the vacuole membrane (tonoplast) to deliver cargoes. Protein components of the canonical intracellular fusion machinery that are conserved across organisms, including Arabidopsis thaliana, include complexes, such as soluble N-ethylmaleimidesensitive factor attachment protein receptors (SNAREs), that catalyze membrane fusion, and homotypic fusion and vacuole protein sorting (HOPS), that serve as adaptors which tether cargo vesicles to target membranes for fusion under the regulation of RAB-GTPases. The mechanisms regulating the recruitment and assembly of tethering complexes are not well-understood, especially the role of RABs in this dynamic regulation. Here, we report the identification of the small synthetic molecule Endosidin17 (E517), which interferes with synthetic, endocytic, and autophagic traffic by impairing the fusion of late endosome compartments with the tonoplast. Multiple independent target identification techniques revealed that E517 targets the VPS35 subunit of the retromer tethering complex, preventing its normal interaction with the Arabidopsis RAB7 homolog RABG3f. E517 interference with VPS35-RABG3f interaction prevents the retromer complex to endosome anchoring, resulting in retention of RABG3f. Using multiple approaches, we show that VPS35-RABG3f-GTP interaction is necessary to trigger downstream events like HOPS complex assembly and fusion of late compartments with the tonoplast. Overall, our results support a role for the interaction of RABG3f-VPS35 as a checkpoint in the control of traffic toward the vacuole.

  • 11.
    Spjut, Sara
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bauer, Johannes
    Storm, Rickard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Stehle, Thilo
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    A Potent Trivalent Sialic Acid Inhibitor of Adenovirus Type 37 Infection of Human Corneal Cells2011In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 50, no 29, p. 6519-6521Article in journal (Refereed)
  • 12.
    Spjut, Sara
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bauer, Johannes
    Interfaculty Institute for Biochemistry, University of Tübingen .
    Storm, Rickard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Stehle, Thilo
    Interfaculty Institute for Biochemistry, University of Tübingen.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Synthesis and evaluation of tri- and tetravalent sialic acid inhibitors of EKC-causing adenovirusesManuscript (preprint) (Other academic)
  • 13.
    Spjut, Sara
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Synthesis and application of a 2-[(4-fluorophenyl)sulfonyl]ethoxy carbonyl (Fsec) protected glycosyl donor in carbohydrate chemistry2010In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 15, no 8, p. 5708-5720Article in journal (Refereed)
    Abstract [en]

    The 2-[(4-fluorophenyl)sulfonyl]ethoxy carbonyl (Fsec) group for protection of hydroxyl groups has been designed, synthesized, and evaluated. Fsec-Cl was readily prepared in 91% yield over three steps and subsequently used to protect 4-fluorobenzyl alcohol in high yield. The Fsec group was cleaved from the resulting model compound under mild basic conditions e.g., 20% piperidine in DMF and was stable under acidic conditions, e.g., neat acetic acid. The Fsec group was used to protect the unreactive 4-OH in a galactose building block that was later used in the synthesis of 6-aminohexyl galabioside.

  • 14.
    Zetterström, Caroline E.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Uusitalo, Pia
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Hinch, Shannon
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Caraballo, Remi
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Grundström, Christin
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Screening for Inhibitors of Acetaldehyde Dehydrogenase (AdhE) from Enterohemorrhagic Escherichia coli (EHEC)2018In: SLAS Discovery, ISSN 2472-5552, Vol. 23, no 8, p. 815-822Article in journal (Refereed)
    Abstract [en]

    Acetaldehyde dehydrogenase (AdhE) is a bifunctional acetaldehyde-coenzyme A (CoA) dehydrogenase and alcohol dehydrogenase involved in anaerobic metabolism in gram-negative bacteria. This enzyme was recently found to be a key regulator of the type three secretion (T3S) system in Escherichia coli. AdhE inhibitors can be used as tools to study bacterial virulence and a starting point for discovery of novel antibacterial agents. We developed a robust enzymatic assay, based on the acetaldehyde-CoA dehydrogenase activity of AdhE using both absorption and fluorescence detection models (Z' > 0.7). This assay was used to screen similar to 11,000 small molecules in 384-well format that resulted in three hits that were confirmed by resynthesis and validation. All three compounds are noncompetitive with respect to acetaldehyde and display a clear dose-response effect with hill slopes of 1-2. These new inhibitors will be used as chemical tools to study the interplay between metabolism and virulence and the role of AdhE in T3S regulation in gram-negative bacteria, and as starting points for the development of novel antibacterial agents.

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