| 1. |
- Karoli, Tomislav, et al.
(författare)
-
Synthesis, biological activity, and preliminary pharmacokinetic evaluation of analogues of a phosphosulfomannan angiogenesis inhibitor (PI-88).
- 2005
-
Ingår i: Journal of medicinal chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:26, s. 8229-36
-
Tidskriftsartikel (refereegranskat)abstract
- The phosphosulfomannan 1 (PI-88) is a mixture of highly sulfated oligosaccharides that is currently undergoing clinical evaluation in cancer patients. As well as its anticancer properties, 1 displays a number of other interesting biological activities. A series of analogues of 1 were synthesized with a single carbon (pentasaccharide) backbone to facilitate structural characterization and interpretation of biological results. In a fashion similar to 1, all compounds were able to inhibit heparanase and to bind tightly to the proangiogenic growth factors FGF-1, FGF-2, and VEGF. The compounds also inhibited the infection of cells and cell-to-cell spread of herpes simplex virus (HSV-1). Preliminary pharmacokinetic data indicated that the compounds displayed different pharmacokinetic behavior compared with 1. Of particular note was the n-octyl derivative, which was cleared 3 times less rapidly than 1 and may provide increased systemic exposure.
|
|
| 2. |
- Renner, Jens, et al.
(författare)
-
The Synthesis and Biological Evaluation of Two Analogues of the C-Riboside Showdomycin
- 2005
-
Ingår i: Australian Journal of Chemistry. ; 58:2, s. 86-93
-
Tidskriftsartikel (refereegranskat)abstract
- Two novel analogues, 2 and 3, of the C-riboside showdomycin (1) have been prepared by exploiting the N-TIPS-substituted pyrrole 7 as a synthetic equivalent for the maleimide C3 anion. The tetraacetate precursor, 12, of target 2 as well as target 3 itself were subjected to single-crystal X-ray analyses. Analogues 2 and 3 as well as showdomycin and its anomer (4) have each been evaluated in various assays for their cytotoxic, anti-bacterial, and anti-viral effects.
|
|
| 3. |
- Adamiak, Beata, et al.
(författare)
-
Herpes simplex virus type 2 glycoprotein g is targeted by the sulfated oligo- and polysaccharide inhibitors of virus attachment to cells
- 2007
-
Ingår i: Journal of Virology. - 0022-538X. ; 81:24, s. 13424-13434
-
Tidskriftsartikel (refereegranskat)abstract
- Variants of herpes simplex virus type 2 (HSV-2) generated by virus passage in GMK-AH1 cells in the presence of the sulfated oligosaccharide PI-88 were analyzed. Many of these variants were substantially resistant to PI-88 in their initial infection of cells and/or their cell-to-cell spread. The major alteration detected in all variants resistant to PI-88 in the initial infection of cells was a frameshift mutation(s) in the glycoprotein G (gG) gene that resulted in the lack of protein expression. Molecular transfer of the altered gG gene into the wild-type background confirmed that the gG-deficient recombinants were resistant to PI-88. In addition to PI-88, all gG-deficient variants of HSV-2 were resistant to the sulfated polysaccharide heparin. The gG-deficient virions were capable of attaching to cells, and this activity was relatively resistant to PI-88. In addition to having a drug-resistant phenotype, the gG-deficient variants were inefficiently released from infected cells. Purified gG bound to heparin and showed the cell-binding activity which was inhibited by PI-88. Many PI-88 variants produced syncytia in cultured cells and contained alterations in gB, including the syncytium-inducing L792P amino acid substitution. Although this phenotype can enhance the lateral spread of HSV in cells, it conferred no virus resistance to PI-88. Some PI-88 variants also contained occasional alterations in gC, gD, gE, gK, and UL24. In conclusion, we found that glycoprotein gG, a mucin-like component of the HSV-2 envelope, was targeted by sulfated oligo- and polysaccharides. This is a novel finding that suggests the involvement of HSV-2 gG in interactions with sulfated polysaccharides, including cell surface glycosaminoglycans.
|
|
| 4. |
- Bergefall, Kicki, 1975, et al.
(författare)
-
Chondroitin sulfate characterized by the E-disaccharide unit is a potent inhibitor of herpes simplex virus infectivity and provides the virus binding sites on gro2C cells.
- 2005
-
Ingår i: The Journal of biological chemistry. - 0021-9258. ; 280:37, s. 32193-9
-
Tidskriftsartikel (refereegranskat)abstract
- Although cell surface chondroitin sulfate (CS) is regarded as an auxiliary receptor for binding of herpes simplex virus to cells, and purified CS chain types A, B, and C are known to interfere poorly or not at all with the virus infection of cells, we have found that CS type E (CS-E), derived from squid cartilage, exhibited potent antiviral activity. The IC(50) values ranged from 0.06 to 0.2 mug/ml and substantially exceeded the antiviral potency of heparin, the known inhibitor of virus binding to cells. Furthermore, in mutant gro2C cells that express CS but not heparan sulfate, CS-E showed unusually high anti-herpes virus activity with IC(50) values of <1 ng/ml. Enzymatic degradation of CS-E with chondroitinase ABC abolished its antiviral activity. CS-E inhibited the binding to cells of the purified virus attachment protein gC. A direct interaction of gC with immobilized CS-E and inhibition of this binding by CS-E oligosaccharide fragments greater than octasaccharide were demonstrated. Likewise, the gro2C-specific CS chains interfered with the binding of viral gC to these cells and were found to contain a considerable proportion (13%) of the E-disaccharide unit, suggesting that this unit is an essential component of the CS receptor for herpes simplex virus on gro2C cells and that the antiviral activity of CS-E was due to interference with the binding of viral gC to a CS-E-like receptor on the cell surface. Knowledge of the determinants of antiviral properties of CS-E will help in the development of inhibitors of herpes simplex virus infections in humans.
|
|
| 5. |
- Ekblad, Maria, 1978, et al.
(författare)
-
Anti-herpes simplex virus activities of two novel disulphated cyclitols.
- 2006
-
Ingår i: Antiviral chemistry & chemotherapy. - 0956-3202. ; 17:2, s. 97-106
-
Tidskriftsartikel (refereegranskat)abstract
- By screening a library of sulphated compounds of low molecular weight, we have found that several cyclitol derivatives, each modified with two sulphate groups in addition to pyrrole and various aromatic moieties, inhibited infectivity of herpes simplex virus (HSV) at concentrations approximately 100 times lower than those toxic for cultured cells. These disulphated cyclitols interfered with HSV-1 attachment to cells, and efficiently reduced the cell-to-cell spread of the virus. This effect is most likely due to their low molecular weight and associated with the compounds' capability to access the narrow intercellular spaces. Furthermore, these disulphated cyclitols also inactivated infectivity of HSV. However, the virus-inactivating activities of these compounds were to some extent diminished in the presence of human cervical secretions or other protein-rich solutions suggesting that disulphated cyclitols may have some features of surfactant-type virucides. In conclusion, this new class of anti-HSV compounds offers potential for further development.
|
|
| 6. |
- Ekblad, Maria, 1978, et al.
(författare)
-
Molecular basis for resistance of herpes simplex virus type 1 mutants to the sulfated oligosaccharide inhibitor PI-88.
- 2007
-
Ingår i: Virology. - : Elsevier BV. - 0042-6822. ; 367:2, s. 244-52
-
Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex virus type 1 variants selected by virus propagation in cultured cells in the presence of the sulfated oligosaccharide PI-88 were analyzed. Many of these variants were substantially resistant to the presence of PI-88 during their initial infection of cells and/or their cell-to-cell spread. Nucleotide sequence analysis revealed that the deletion of amino acids 33-116 of gC but not lack of gC expression provided the virus with selective advantage to infect cells in the presence of PI-88. Purified gC (Delta33-116) was more resistant to PI-88 than unaltered protein in its binding to cells. Alterations that partly contributed to the virus resistance to PI-88 in its cell-to-cell spread activity were amino acid substitutions Q27R in gD and R770W in gB. These results suggest that PI-88 targets several distinct viral glycoproteins during the course of initial virus infection and cell-to-cell spread.
|
|
| 7. |
- Müller Kratz, Jadel, et al.
(författare)
-
Anti-HSV-1 and anti-HIV-1 activity of gallic acid and pentyl gallate.
- 2008
-
Ingår i: Memórias do Instituto Oswaldo Cruz. - 1678-8060. ; 103:5, s. 437-42
-
Tidskriftsartikel (refereegranskat)abstract
- The synthetic n-alkyl esters of gallic acid (GA), also known as gallates, especially propyl, octyl and dodecyl gallates, are widely employed as antioxidants by food and pharmaceutical industries. The inhibitory effects of GA and 15 gallates on Herpes Simplex Virus type 1 (HSV-1) and Human Immunodeficiency Virus (HIV-1) replication were investigated here. After a preliminary screening of these compounds, GA and pentyl gallate (PG) seemed to be the most active compounds against HSV-1 replication and their mode of action was characterized through a set of assays, which attempted to localize the step of the viral multiplication cycle where impairment occurred. The detected anti-HSV-1 activity was mediated by the inhibition of virus attachment to and penetration into cells, and by virucidal properties. Furthermore, an anti-HIV-1 activity was also found, to different degrees. In summary, our results suggest that both compounds could be regarded as promising candidates for the development of topical anti-HSV-1 agents, and further studies concerning the anti-HIV-1 activity of this group of molecules are merited.
|
|
| 8. |
- Müller Kratz, Jadel, et al.
(författare)
-
Evaluation of anti-HSV-2 activity of gallic acid and pentyl gallate.
- 2008
-
Ingår i: Biological & pharmaceutical bulletin. - 0918-6158. ; 31:5, s. 903-7
-
Tidskriftsartikel (refereegranskat)abstract
- The synthetic n-alkyl esters of gallic acid, also known as gallates, are widely employed as antioxidants by food and pharmaceutical industries. Besides the antioxidant activity, other biological activities have been described for this group of molecules, mainly anticancer, antibacterial and antifungal properties. In the present study, the anti-herpes simplex virus (HSV)-2 activity of gallic acid and pentyl gallate was evaluated followed by the determination of the site of antiviral activity of these compounds. Our results demonstrated that both compounds reduced HSV-2 replication in a concentration-dependent manner when either incubated with the virus prior to the addition of the mixture to cells, or added to and incubated with cells after their infection. In summary, the anti-HSV-2 activity of gallic acid and pentyl gallate was ascribed to their virucidal effect on virus particles, a change that was likely accompanied by partial inhibition of the virus attachment to cells and its subsequent cell-to-cell spread activity. This suggests that these compounds can be regarded as promising candidates for development as topical anti-HSV-2 agents.
|
|
| 9. |
- Uyama, Toru, et al.
(författare)
-
Chondroitin 4-O-sulfotransferase-1 regulates E disaccharide expression of chondroitin sulfate required for herpes simplex virus infectivity.
- 2006
-
Ingår i: The Journal of biological chemistry. - 0021-9258. ; 281:50, s. 38668-74
-
Tidskriftsartikel (refereegranskat)abstract
- We have demonstrated a defect in expression of chondroitin 4-O-sulfotransferase-1 (C4ST-1) in murine sog9 cells, which are poorly sensitive to infection by herpes simplex virus type 1 (HSV-1). Sog9 cells were previously isolated as CS-deficient cells from gro2C cells, which were partially resistant to HSV-1 infection and defective in the expression of heparan sulfate (HS) because of a splice site mutation in the EXT1 gene encoding the HS-synthesizing enzyme. Here we detected a small amount of CS chains in sog9 cells with a drastic decrease in 4-O-sulfation compared with the parental gro2C cells. RT-PCR revealed that sog9 cells had a defect in the expression of C4ST-1 in addition to EXT1. Gel filtration analysis showed that the decrease in the amount of CS in sog9 cells was the result of a reduction in the length of CS chains. Transfer of C4ST-1 cDNA into sog9 cells (sog9-C4ST-1) restored 4-O-sulfation and amount of CS, verifying that sog9 cells had a specific defect in C4ST-1. Furthermore, the expression of C4ST-1 rendered sog9 cells significantly more susceptible to HSV-1 infection, suggesting that CS modified by C4ST-1 is sufficient for the binding and infectivity of HSV-1. Analysis of CS chains of gro2C and sog9-C4ST-1 cells revealed a considerable proportion of the E disaccharide unit, consistent with our recent finding that this unit is an essential component of the HSV receptor. These results suggest that C4ST-1 regulates the expression of the E disaccharide unit and the length of CS chains, the features that facilitate infection of cells by HSV-1.
|
|
