1.
Aplander, Karolina, et al.
(author)
Molecular wipes : application to epidemic keratoconjuctivitis
2011
In: Journal of Medicinal Chemistry. - Easton, Pa. : American Chemical Society. - 0022-2623 .- 1520-4804. ; 54:19, s. 6670-6675
Journal article (peer-reviewed) abstract
Epidemic keratoconjunctivitis (EKC) is a severe disease of the eye, caused by members of the Adenoviridae (Ad) family, with symptoms such as keratitis, conjunctivitis, pain, edema, and reduced vision that may last for months or years. There are no vaccines or antiviral drugs available to prevent or treat EKC. It was found previously that EKC-causing Ads use sialic acid as a cellular receptor and demonstrated that soluble, sialic acid-containing molecules can prevent infection. In this study, multivalent sialic acid constructs based on 10,12-pentacosadiynoic acid (PDA) have been synthesized, and these constructs are shown to be efficient inhibitors of Ad binding (IC(50) = 0.9 mu M) and Ad infectivity (IC(50) = 0.7 mu M). The mechanism of action is to aggregate virus particles and thereby prevent them from binding to ocular cells. Such formulations may be used for topical treatment of adenovirus-caused EKC.
2.
Persson, Andrea, et al.
(author)
Xyloside-primed chondroitin sulfate/dermatan sulfate from breast carcinoma cells with a defined disaccharide composition has cytotoxic effects in vitro
2016
In: Journal of Biological Chemistry. - 1083-351X. ; 291:28, s. 14871-14882
Journal article (peer-reviewed) abstract
We have previously reported that the xyloside 2-(6-hydroxynaphthyl) β-D-xylopyranoside (XylNapOH), in contrast to 2-naphthyl β-D-xylopyranoside (XylNap), specifically reduces tumor growth both in vitro and in vivo. Although there are indications that this could be mediated by the xyloside-primed glycosaminoglycans (GAGs) and that these differ in composition depending on xyloside and cell type, detailed knowledge regarding a structure-function relationship is lacking. In this study, we isolated XylNapOH- and XylNap-primed GAGs from a breast carcinoma cell line, HCC70, and a breast fibroblast cell line, CCD-1095Sk, and demonstrated that both XylNapOH- and XylNap-primed chondroitin sulfate/dermatan sulfate (CS/DS) GAGs derived from HCC70 cells had a cytotoxic effect on HCC70 cells and CCD-1095Sk cells. The cytotoxic effect appeared to be mediated by induction of apoptosis and was inhibited in a concentration-dependent manner by the XylNap-primed heparan sulfate (HS) GAGs. In contrast, neither the CS/DS nor the HS derived from CCD-1095Sk cells primed on XylNapOH or XylNap had any effect on the growth of HCC70 cells or CCD-105Sk cells. These observations were related to the disaccharide composition of the XylNapOH- and XylNap-primed GAGs, which differed considerably between the two cell lines, but was similar when the GAGs were derived from the same cell line. To our knowledge, this is the first report on cytotoxic effects mediated by CS/DS.
3.
Siegbahn, Anna, et al.
(author)
Exploration of the active site of β4GalT7: modifications of the aglycon of aromatic xylosides.
2015
In: Organic and Biomolecular Chemistry. - : Royal Society of Chemistry (RSC). - 1477-0539 .- 1477-0520. ; 13:11, s. 3351-3362
Journal article (peer-reviewed) abstract
Proteoglycans (PGs) are macromolecules that consist of long linear polysaccharides, glycosaminoglycan (GAG) chains, covalently attached to a core protein by the carbohydrate xylose. The biosynthesis of GAG chains is initiated by xylosylation of the core protein followed by galactosylation by the galactosyltransferase β4GalT7. Some β-d-xylosides, such as 2-naphthyl β-d-xylopyranoside, can induce GAG synthesis by serving as acceptor substrates for β4GalT7 and by that also compete with the GAG synthesis on core proteins. Here we present structure-activity relationships for β4GalT7 and xylosides with modifications of the aromatic aglycon, using enzymatic assays, cell studies, and molecular docking simulations. The results show that the aglycons reside on the outside of the active site of the enzyme and that quite bulky aglycons are accepted. By separating the aromatic aglycon from the xylose moiety by linkers, a trend towards increased galactosylation with increased linker length is observed. The galactosylation is influenced by the identity and position of substituents in the aromatic framework, and generally, only xylosides with β-glycosidic linkages function as good substrates for β4GalT7. We also show that the galactosylation ability of a xyloside is increased by replacing the anomeric oxygen with sulfur, but decreased by replacing it with carbon. Finally, we propose that reaction kinetics of galactosylation by β4GalT7 is dependent on subtle differences in orientation of the xylose moiety.
4.
Tykesson, Emil, et al.
(author)
Deciphering the mode of action of the processive polysaccharide modifying enzyme dermatan sulfate epimerase 1 by hydrogen-deuterium exchange mass spectrometry
2016
In: Chemical Science. - : Royal Society of Chemistry (RSC). - 2041-6539 .- 2041-6520. ; 7:2, s. 1447-1456
Journal article (peer-reviewed) abstract
Distinct from template-directed biosynthesis of nucleic acids and proteins, the enzymatic synthesis of heterogeneous polysaccharides is a complex process that is difficult to study using common analytical tools. Therefore, the mode of action and processivity of those enzymes are largely unknown. Dermatan sulfate epimerase 1 ( DS-epi1) is the predominant enzyme during the formation of iduronic acid residues in the glycosaminoglycan dermatan sulfate. Using recombinant DS-epi1 as a model enzyme, we describe a tandem mass spectrometry-based method to study the mode of action of polysaccharide processing enzymes. The enzyme action on the substrate was monitored by hydrogen-deuterium exchange mass spectrometry and the sequence information was then fed into mathematical models with two different assumptions of the mode of action for the enzyme: processive reducing end to non-reducing end, and processive non-reducing end to reducing end. Model data was scored by correlation to experimental data and it was found that DS-epi1 attacks its substrate on a random position, followed by a processive mode of modification towards the non-reducing end and that the substrate affinity of the enzyme is negatively affected by each additional epimerization event. It could also be shown that the smallest active substrate was the reducing end uronic acid in a tetrasaccharide and that octasaccharides and longer oligosaccharides were optimal substrates. The method of using tandem mass spectrometry to generate sequence information of the complex enzymatic products in combination with in silico modeling can be potentially applied to study the mode of action of other enzymes involved in polysaccharide biosynthesis.
5.
Aili, Ulrika, et al.
(author)
Antiproliferative effects of peracetylated naphthoxylosides.
2009
In: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X. ; 19, s. 1763-1766
Journal article (peer-reviewed) abstract
The antiproliferative activity, and the capability of priming of glycosaminoglycan chains, of two series of peracetylated mono- and bis-xylosylated dihydroxynaphthalenes have been investigated for normal HFL-1 cells, as well as transformed T24 cells, and compared to the unprotected analogs. Our data show increased antiproliferative activity upon peracetylation, but a loss of selectivity towards T24 cells.
6.
Bozzola, Tiago, et al.
(author)
Sialic Acid 4-N-Piperazine and Piperidine Derivatives Bind with High Affinity to the P. mirabilis Sialic Acid Sodium Solute Symporter
2022
In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 17:23
Journal article (peer-reviewed) abstract
In search for novel antibacterial compounds, bacterial sialic acid uptake inhibition represents a promising strategy. Sialic acid plays a critical role for growth and colonisation of several pathogenic bacteria, and its uptake inhibition in bacteria was recently demonstrated to be a viable strategy by targeting the SiaT sodium solute symporters from Proteus mirabilis and Staphylococcus aureus. Here we report the design, synthesis and evaluation of potential sialic acid uptake inhibitors bearing 4-N-piperidine and piperazine moieties. The 4-N-derivatives were obtained via 4-N-functionalization with piperidine and piperazine nucleophiles in an efficient direct substitution of the 4-O-acetate of Neu5Ac. Evaluation for binding to bacterial transport proteins with nanoDSF and ITC revealed compounds possessing nanomolar affinity for the P. mirabilis SiaT symporter. Computational analyses indicate the engagement of a previously untargeted portion of the binding site.
7.
Bozzola, Tiago, et al.
(author)
Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth
2022
In: Acs Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 17:7, s. 1890-1900
Journal article (peer-reviewed) abstract
Antibiotic resistance is a major worldwide concern, and new drugs with mechanistically novel modes of action are urgently needed. Here, we report the structure-based drug design, synthesis, and evaluation in vitro and in cellular systems of sialic acid derivatives able to inhibit the bacterial sialic acid symporter SiaT. We designed and synthesized 21 sialic acid derivatives and screened their affinity for SiaT by a thermal shift assay and elucidated the inhibitory mechanism through binding thermodynamics, computational methods, and inhibitory kinetic studies. The most potent compounds, which have a 180-fold higher affinity compared to the natural substrate, were tested in bacterial growth assays and indicate bacterial growth delay in methicillin-resistant Staphylococcus aureus. This study represents the first example and a promising lead in developing sialic acid uptake inhibitors as novel antibacterial agents.
8.
9.
Jacobsson, Mårten, et al.
(author)
Effects of oxygen-sulfur substitution on glycosaminoglycan-priming naphthoxylosides.
2007
In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896. ; 15:15, s. 5283-5299
Journal article (peer-reviewed) abstract
Three series of sulfur-containing analogs to the selectively antiproliferative 2-(6-hydroxynaphthyl) β-d-xylopyranoside were synthesized and their biological properties investigated. A short, general route to hydroxynaphthyl disulfides from dihydroxynaphthalenes was developed to utilize the disulfide bond as a sulfur-selective protecting group to enable the orthogonal protection of hydroxyls and thiols. The results indicate that hydrophobic, uncharged oxygen–sulfur substituted naphthoxylosides are taken up by cells and initiate priming of GAG chains to a greater extent compared to the oxygen analogs. No correlation between priming ability and antiproliferative activity was observed.
10.
Jacobsson, Mårten, et al.
(author)
Selective antiproliferative activity of hydroxynaphthyl-beta-D-xylosides
2006
In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 49:6, s. 1932-1938
Journal article (peer-reviewed) abstract
The antiproliferative activity of the 14 isomeric monoxylosylated dihydroxynaphthalenes has been tested in vitro toward normal HFL-1 and 3T3 A31 cells as well as transformed T24 and 3T3 SV40 cells. The antiproliferative effect toward HFL-1 cells was correlated with the polarity of the compounds. However, in the case of transformed T24 cells, some compounds showed a clearly different behavior resulting in a selective antiproliferative effect. No such correlation was found for normal 3T3 A31 or virus transformed 3T3 SV40 cells, nor for the free aglycon. These results suggest that the antiproliferative activity shown by naphthoxylosides is diverse in different cell lines and dependent on the nature of the aglycon. The anti proliferative effect of 2- (6-hydroxynaphthyl)-beta-D-xylopyranoside, in contrast to inactive 2-naphthyl-beta-D-xylopyranoside, on T24 cells was accompanied by increased apoptosis as indicated by a TUNEL assay.
