Ulrik Hillaert

Publications of Ulrik Hillaert

• Structure-activity relationship of cinnamaldehyde analogs as inhibitors of AI-2 based quorum sensing and their effect on virulence of Vibrio spp.

  Authors: Gilles Brackman, Shari Celen, Ulrik Hillaert, Serge Van Calenbergh, Paul Cos, Louis Maes, Hans J Nelis, Tom Coenye

  PloS one. 01/2011; 6(1):e16084.

  Many bacteria, including Vibrio spp., regulate virulence gene expression in a cell-density dependent way through a communication process termed quorum sensing (QS). Hence, interfering with QS couldMany bacteria, including Vibrio spp., regulate virulence gene expression in a cell-density dependent way through a communication process termed quorum sensing (QS). Hence, interfering with QS could be a valuable novel antipathogenic strategy. Cinnamaldehyde has previously been shown to inhibit QS-regulated virulence by decreasing the DNA-binding ability of the QS response regulator LuxR. However, little is known about the structure-activity relationship of cinnamaldehyde analogs. By evaluating the QS inhibitory activity of a series of cinnamaldehyde analogs, structural elements critical for autoinducer-2 QS inhibition were identified. These include an α,β unsaturated acyl group capable of reacting as Michael acceptor connected to a hydrophobic moiety and a partially negative charge. The most active cinnamaldehyde analogs were found to affect the starvation response, biofilm formation, pigment production and protease production in Vibrio spp in vitro, while exhibiting low cytotoxicity. In addition, these compounds significantly increased the survival of the nematode Caenorhabditis elegans infected with Vibrio anguillarum, Vibrio harveyi and Vibrio vulnificus. Several new and more active cinnamaldehyde analogs were discovered and they were shown to affect Vibrio spp. virulence factor production in vitro and in vivo. Although ligands for LuxR have not been identified so far, the nature of different cinnamaldehyde analogs and their effect on the DNA binding ability of LuxR suggest that these compounds act as LuxR-ligands.

• Design, synthesis and evaluation of high-affinity binders for the celiac disease associated HLA-DQ2 molecule.

  Authors: Varsha V Kapoerchan, Martina Wiesner, Ulrik Hillaert, Jan W Drijfhout, Mark Overhand, Philippe Alard, Gijs A van der Marel, Hermen S Overkleeft, Frits Koning

  Molecular immunology. 12/2009;

  Celiac disease is caused by uncontrolled CD4 T-cell responses directed to wheat-derived gluten peptides bound to the disease predisposing HLA-DQ molecules. The only available treatment is a life-longCeliac disease is caused by uncontrolled CD4 T-cell responses directed to wheat-derived gluten peptides bound to the disease predisposing HLA-DQ molecules. The only available treatment is a life-long gluten-free diet which is complicated by the widespread use of wheat-derived gluten in the food industry. As the binding of gluten-derived peptides is a prerequisite for the induction of the inflammatory T-cell response, blockers that would prevent gluten peptide binding to the HLA-DQ molecules might be used as an alternative to the gluten-free diet. In the present study we have analyzed the binding properties of a set of previously identified natural ligands for HLA-DQ2, the primary disease predisposing allele. An in silico method, Epibase, ranked these peptides and the top one, a peptide with a nine amino acid core FVAEYEPVL, was measured among these peptides as the peptide with the highest binding affinity for HLA-DQ2. In a stepwise approach we subsequently tested the impact of N-terminal extensions and systematic single amino acid substitutions within the core of this peptide which revealed that an N-terminal extension with the tripeptide sequence ADA increased binding affinity 5- to 6-fold. In addition the substitution analysis indicated which amino acids were most preferred at anchor residues in the lead peptide, generally leading to an increase of binding affinity with a factor of 2. Next we tested which combinations of such preferred amino acids yielded the best results. The combined results indicate that a peptide with sequence ADAYDYESEELFAA (core in bold) had superior binding properties. This peptide was chosen as a lead peptide for further optimization with non-natural amino acids at the p1 position, since molecular modeling indicated that none of the natural amino acids is able to optimally occupy the p1 pocket. A set of 8 non-proteinogenic amino acids was designed, synthesized and incorporated in the lead peptide (and in two control peptides) and tested for binding to HLA-DQ2. The results indicate that the effect of the incorporation of these non-proteinogenic amino acids depended on the peptide in which they were incorporated and that the maximum increase in binding affinity obtained was approximately 2-fold. Altogether lead sequences were obtained that have a binding affinity for HLA-DQ2 that is 100- to 200-fold higher compared to that of the gluten-derived peptide that has the highest affinity for HLA-DQ2. Such peptides are candidate lead peptides for further optimization. Our results, however, also indicate that in order to obtain further significant increases in binding affinity alternative approaches will have to be explored.

• Receptor-Mediated Targeting of Cathepsins in Professional Antigen Presenting Cells.

  Authors: Ulrik Hillaert, Martijn Verdoes, Bogdan I Florea, Anastasios Saragliadis, Kim L L Habets, Johan Kuiper, Serge Van Calenbergh, Ferry Ossendorp, Gijsbert A van der Marel, Christoph Driessen, Hermen S Overkleeft

  Angewandte Chemie (International ed. in English). 02/2009;

• Use of quorum sensing inhibitors to interfere with biofilm formation and development in Burkholderia multivorans and Burkholderia cenocepacia.

  Authors: Gilles Brackman, Ulrik Hillaert, Serge Van Calenbergh, Hans J Nelis, Tom Coenye

  Research in microbiology. 01/2009;

  Burkholderia cepacia complex strains are opportunistic pathogens causing life-threatening infections in cystic fibrosis patients. Burkholderia cepacia complex strains are resistant to manyBurkholderia cepacia complex strains are opportunistic pathogens causing life-threatening infections in cystic fibrosis patients. Burkholderia cepacia complex strains are resistant to many antimicrobial agents and commonly produce biofilms in vitro and in vivo. This contributes to their virulence and makes Burkholderia infections difficult to treat. Recently, the quorum sensing (QS) system of Burkholderia spp. has been found to affect their biofilm-forming ability, making it an attractive target for antimicrobial therapy. However, detailed information about the anti-biofilm effect of these compounds is still lacking. In the present study, we evaluated the anti-biofilm effect of several known QS inhibitors. The effect on Burkholderia spp. biofilm formation was examined using crystal violet, resazurin and SYTO9 staining, confocal laser scanning microscopy as well as plating. When used at subinhibitory concentrations, several compounds interfered with biofilm formation by Burkholderia spp. Our results suggest that the QS inhibitors affect later stages of biofilm formation and detachment.

• 6'-derivatised alpha-GalCer analogues capable of inducing strong CD1d-mediated Th1-biased NKT cell responses in mice.

  Authors: Matthias Trappeniers, Katrien Van Beneden, Tine Decruy, Ulrik Hillaert, Bruno Linclau, Dirk Elewaut, Serge Van Calenbergh

  Journal of the American Chemical Society. 01/2009; 130(49):16468-9.

• Azido-BODIPY acid reveals quantitative Staudinger-Bertozzi ligation in two-step activity-based proteasome profiling.

  Authors: Martijn Verdoes, Bogdan I Florea, Ulrik Hillaert, Lianne I Willems, Wouter A van der Linden, Myra Sae-Heng, Dmitri V Filippov, Alexei F Kisselev, Gijsbert A van der Marel, Herman S Overkleeft

  Chembiochem : a European journal of chemical biology. 08/2008; 9(11):1735-8.

• Fungicidal activity of truncated analogues of dihydrosphingosine.

  Authors: Karin Thevissen, Ulrik Hillaert, Els M K Meert, Kuen K Chow, Bruno P A Cammue, Serge Van Calenbergh, Isabelle E J A François

  Bioorganic & medicinal chemistry letters. 07/2008; 18(13):3728-30.

  The minimal fungicidal concentration (MFC) of dihydrosphingosine (DHS), phytosphingosine (PHS), and five short-chain DHS derivatives was determined for Candida albicans and Candida glabrata. In thisThe minimal fungicidal concentration (MFC) of dihydrosphingosine (DHS), phytosphingosine (PHS), and five short-chain DHS derivatives was determined for Candida albicans and Candida glabrata. In this respect, a C15- and a C17-homologue of DHS showed a 2- to 10-fold decreased MFC as compared to native DHS (i.e. C18-DHS). DHS derivatives that were active, that is, comprising 12, 15, 17, or 18 carbon atoms, induced accumulation of reactive oxygen species (ROS) in C. albicans.

• Synthesis of beta- and gamma-oxa isosteres of fosmidomycin and FR900098 as antimalarial candidates.

  Authors: Timothy Haemers, Jochen Wiesner, Dirk Giessmann, Thomas Verbrugghen, Ulrik Hillaert, Regina Ortmann, Hassan Jomaa, Andreas Link, Martin Schlitzer, Serge Van Calenbergh

  Bioorganic & medicinal chemistry. 04/2008; 16(6):3361-71.

  To expand the structure-activity relationships of fosmidomycin and FR900098, two potent antimalarials interfering with the MEP-pathway, we decided to replace a methylene group in beta-position of theTo expand the structure-activity relationships of fosmidomycin and FR900098, two potent antimalarials interfering with the MEP-pathway, we decided to replace a methylene group in beta-position of the phosphonate moiety of these leads by an oxygen atom. beta-oxa-FR900098 (11) proved equally active as the parent compound. When applied to 4-[hydroxyl(methyl)amino]-4-oxobutyl phosphonic acid, featuring a hydroxamate instead of the retrohydroxamate moiety, a beta-oxa modification yielded a derivative (13) with superior activity against the Plasmodium falciparum 3D7 strain than fosmidomycin, while a gamma-oxa modification resulted in less active derivatives. A bis(pivaloyloxymethyl)ester of phosphonate 13 proved twice as active in inhibiting cultured parasites as a similar prodrug of FR900098.

• Acetylene functionalized BODIPY dyes and their application in the synthesis of activity based proteasome probes.

  Authors: Martijn Verdoes, Ulrik Hillaert, Bogdan I Florea, Myra Sae-Heng, Martijn D P Risseeuw, Dmitri V Filippov, Gijsbert A van der Marel, Herman S Overkleeft

  Bioorganic & medicinal chemistry letters. 12/2007; 17(22):6169-71.

  The synthesis of three acetylene functionalized BODIPY dyes is described. These dyes are used to fluorescently modify an azido functionalized epoxomicin analogue employing the Huisgen 1,3-dipolarThe synthesis of three acetylene functionalized BODIPY dyes is described. These dyes are used to fluorescently modify an azido functionalized epoxomicin analogue employing the Huisgen 1,3-dipolar cycloaddition, resulting in a panel of fluorescent epoxomicin derived proteasome probes.

• Synthesis and biological evaluation of novel PDMP analogues.

  Authors: Ulrik Hillaert, Swetlana Boldin-Adamsky, Jef Rozenski, Roger Busson, Anthony H Futerman, Serge Van Calenbergh

  Bioorganic & medicinal chemistry. 09/2006; 14(15):5273-84.

  A new series of hybrid PDMP analogues, based both on PDMP and styryl analogues of natural ceramide, has been synthesized from D-serine. The synthetic route was developed such that future introductionA new series of hybrid PDMP analogues, based both on PDMP and styryl analogues of natural ceramide, has been synthesized from D-serine. The synthetic route was developed such that future introduction of different aryl groups is straightforward. Biological evaluation, both in vitro on rat liver Golgi fractions as well as in HEK-293 and COS-7 cells, revealed two lead compounds with comparable inhibitory potency as PDMP, which could be elaborated to more potent inhibitors.

• Synthesis of a versatile (S)-3-(hydroxymethyl)butane-1,2,4-triol building block and its application for the stereoselective synthesis of N-homoceramides.

  Authors: Ulrik Hillaert, Serge Van Calenbergh

  Organic letters. 01/2006; 7(26):5769-72.

  [structures: see text] A versatile (S)-3-(hydroxymethyl)butane-1,2,4-triol building block has been synthesized starting from D-isoascorbic acid, a common food preservative. The key transformation in[structures: see text] A versatile (S)-3-(hydroxymethyl)butane-1,2,4-triol building block has been synthesized starting from D-isoascorbic acid, a common food preservative. The key transformation in this approach was the introduction of branching through a high yield and fully regioselective epoxide opening. This flexible synthon has been elaborated to a new class of (dihydro-)N-homo(phyto)ceramides.

• Synthesis, radiosynthesis, in vitro and preliminary in vivo evaluation of biphenyl carboxylic and hydroxamic matrix metalloproteinase (MMP) inhibitors as potential tumor imaging agents.

  Authors: Ruth Oltenfreiter, Ludovicus Staelens, Ulrik Hillaert, An Heremans, Agnes Noël, Francis Frankenne, Guido Slegers

  Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine. 07/2005; 62(6):903-13.

  Excess matrix degradation is one of the hallmarks of cancer and is an important factor in the process of tumor progression. It is implicated in invasion, metastasis, growth, angiogenesis andExcess matrix degradation is one of the hallmarks of cancer and is an important factor in the process of tumor progression. It is implicated in invasion, metastasis, growth, angiogenesis and migration. Many characteristics of matrix metalloproteinases (MMPs) make them attractive therapeutic and diagnostic targets. MMP expression is upregulated at the tumor site, with localization of activity in the tumor or the surrounding stroma, providing a target for medical imaging techniques. Radioiodinated carboxylic and hydroxamic MMP inhibitors 2-(4'-[123I] iodo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid (9) and 2-(4'-[123I] iodo-biphenyl-4-sulfonylamino)-3-methyl-butyramide (11), their unlabelled standards and precursors were synthesized. Radioiodination was conducted by electrophilic aromatic substitution of the tributylstannyl precursors and resulted in radiochemical yields of 70+/-5% (n=6) and 60+/-5% (n=4), respectively. In vitro zymography and enzyme assays showed for both hydroxamic acid and carboxylic acid compounds a good inhibition activity and a high selectivity for MMP-2. In vivo biodistribution in NMRI mice showed no long-term accumulation in organs and the possibility to accumulate in the tumor in a later phase of this study.

• 2,5-Bis-(2-hydroxybenzoylamino)pentanoic acid, a salicylic acid-metabolite isolated from chicken: characterization and independent synthesis.

  Authors: Ulrik Hillaert, Kris Baert, Jef Rozenski, Siska Croubels, Denis De Keukeleire, Patrick De Backer, Serge Van Calenbergh

  Bioorganic & medicinal chemistry letters. 03/2003; 13(3):335-7.

  From excreta of chickens that had been treated with sodium salicylate, a new compound was detected and identified as a double conjugated ornithine metabolite. The structural assignment of thisFrom excreta of chickens that had been treated with sodium salicylate, a new compound was detected and identified as a double conjugated ornithine metabolite. The structural assignment of this metabolite was further confirmed by an independent efficient 3-step synthesis from ornithine.

• Synthesis of homoceramides, novel ceramide analogues, and their lack of effect on the growth of hippocampal neurons.

  Authors: Steven De Jonghe, Inge Lamote, Krishnan Venkataraman, Swetlana A Boldin, Ulrik Hillaert, Jef Rozenski, Chris Hendrix, Roger Busson, Denis De Keukeleire, Serge Van Calenbergh, Anthony H Futerman, Piet Herdewijn

  The Journal of organic chemistry. 03/2002; 67(3):988-96.

  The synthesis of a new series of D-erythro-homoceramide analogues is described. Several synthetic approaches were investigated. Homoceramides can be successfully synthesized from L-homoserine asThe synthesis of a new series of D-erythro-homoceramide analogues is described. Several synthetic approaches were investigated. Homoceramides can be successfully synthesized from L-homoserine as chiral building block and a protected Weinreb-amide as a key intermediate. The synthesis of short-chain analogues with a heptyl side chain, as well as with a phenyl residue in the sphingoid part (instead of the naturally occurring tridecyl side chain), was effected. The homoceramides 15-17 and 24 were investigated for their potential to reverse the inhibitory effect of fumonisin B(1) on axonal growth. Unfortunately, none of the tested compounds showed any biological activity due to their lack of metabolism to glucosylhomoceramide.