Hanne L. Ziegler
University of Copenhagen
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Featured researches published by Hanne L. Ziegler.
ChemBioChem | 2010
Christian A. Olsen; Hanne L. Ziegler; Hanne Mørck Nielsen; Niels Frimodt-Møller; Jerzy W. Jaroszewski; Henrik Franzyk
While natural host-defense antimicrobial peptides (AMPs) and analogues thereof have been investigated intensely in the last two decades with the purpose of combating the still increasing threat from emerging multiresistant pathogenic microbes, 2] compounds with peptidomimetic backbones have received considerable attention due to their superior stability against proteolytic enzymes. 4] Typically, studies of peptidomimetic AMP analogues have involved a brief microbiological evaluation of an array of oligomers, and only occasionally has testing been performed across a broader range of microorganisms or involved systematic structure–activity relationship (SAR) studies. Such investigations have proven fruitful for a-peptidic AMPs, 18] and might reveal unexpected lead structures and selectivity profiles when applied to peptidomimetics as well. Therefore, we have performed a more rigorous microbiological evaluation as well as toxicity profiling of a series of oligomers based on our b-peptoid–peptide hybrid backbone architecture. 20] Antimicrobial activities were determined alongside the archetypal cationic AMP magainin-2 and its clinically tested derivative pexiganan against a series of five important pathogens belonging to different classes. The obtained SAR data were subsequently correlated with various measurements of toxicity towards mammalian cells. Thereby we were able to derive useful trends for the future design of antibacterial and antifungal peptidomimetic constructs with potential for enhanced selectivity. Three subclasses 1 a–3 d (Scheme 1) were originally designed to address the general effects of length, type of cationic side chains, and presence of a-chirality in the b-peptoid residues. These series had previously been confirmed to possess membrane activity, as indicated by testing for hemolytic and prehemolytic effects, as well as by calcein release experiments with model liposomes, albeit the interaction of these compounds with intracellular targets cannot be ruled out based on our data. The all-aliphatic compound 4 and the mixed aromatic–aliphatic chimera 5 were included to address the importance of lipophilicity and type of cationic residue. Finally, we included three 5/6-carboxyfluorescein-labeled oligomers (6–8) to assess the influence of the presence of this widely used fluorophore on the antimicrobial activity, which might have important implications for confocal fluorescence microscopy studies of the interaction of labeled compounds with live bacteria. The chimeras 4–8 were of dodecamer length to minimize undesired mammalian cell toxicity that might be observed with increasing length. This compound collection was tested against a variety of clinically relevant pathogens and human red blood cells (Table 1). Scheme 1. Chemical structures of the examined hybrid oligomers. The abbreviations used for the b-peptoid units were adapted from the abbreviations commonly used for peptoids (i.e. , N-alkylglycines), 7] by adding the b-prefix. bNspe = N-(S)-1-phenylethyl-balanine, bNphe =b-N-phenylalanine, bNsce = N-(S)-1-cyclohexylethyl-b-alanine, hArg = homoarginine, CF = 5/6-carboxyfluoresceinoyl.
Antimicrobial Agents and Chemotherapy | 2002
Hanne L. Ziegler; Dan Staerk; Jette Christensen; Lars Hviid; Henry Hägerstrand; Jerzy W. Jaroszewski
ABSTRACT Lupeol, which shows in vitro inhibitory activity against Plasmodium falciparum 3D7 strain with a 50% inhibitory concentration (IC50) of 27.7 ± 0.5 μM, was shown to cause a transformation of the human erythrocyte shape toward that of stomatocytes. Good correlation between the IC50 value and the membrane curvature changes caused by lupeol was observed. Preincubation of erythrocytes with lupeol, followed by extensive washing, made the cells unsuitable for parasite growth, suggesting that the compound incorporates into erythrocyte membrane irreversibly. On the other hand, lupeol-treated parasite culture continued to grow well in untreated erythrocytes. Thus, the antiplasmodial activity of lupeol appears to be indirect, being due to stomatocytic transformation of the host cell membrane and not to toxic effects via action on a drug target within the parasite. A number of amphiphiles that cause stomatocyte formation, but not those causing echinocyte formation, were shown to inhibit growth of the parasites, apparently via a mechanism similar to that of lupeol. Since antiplasmodial agents that inhibit parasite growth through erythrocyte membrane modifications must be regarded as unsuitable as leads for development of new antimalarial drugs, care must be exercised in the interpretation of results of screening of plant extracts and natural product libraries by an in vitro Plasmodium toxicity assay.
Antimicrobial Agents and Chemotherapy | 2004
Hanne L. Ziegler; Harald S. Hansen; Dan Staerk; Søren Christensen; Henry Hägerstrand; Jerzy W. Jaroszewski
ABSTRACT The well-known antiparasitic compound licochalcone A is a potent membrane-active agent that transforms normal erythrocytes into echinocytes in parallel with the inhibition of growth of Plasmodium falciparum cultures, the in vitro antiplasmodial effect apparently being an indirect effect on the host cell. In vitro experiments with synchronous cultures demonstrate that inhibition of invasion is the principal mechanism of growth inhibition. The erythrocyte membrane-modifying effect was also transiently observed in vivo in mice after intravenous administration.
Journal of Natural Products | 2008
Kennett Sprogøe; Dan Staerk; Hanne L. Ziegler; Thomas Høgh Jensen; Søren Boe Holm-Møller; Jerzy W. Jaroszewski
Despite recent demonstration of the power of HPLC-PDA-MS-SPE-NMR (high-performance liquid chromatography-photodiode-array detection-mass spectrometry-solid-phase extraction-nuclear magnetic resonance) in structure determination of natural products directly from minute amounts of crude extracts, this technique leaves chirality of the compounds uncharacterized. In this work we demonstrate that postcolumn SPE is a useful method of analyte concentration and accumulation not only for NMR but also for CD (circular dichroism) spectroscopy. Thus, use of HPLC-PDA-MS-SPE-NMR in combination with CD allowed rapid detection of ( R)-(-)-gossypol [( R)- 1] in Thespesia danis, providing a very rare example of the predominance of the levorotatory enantiomer of gossypol. Enantioselectivity of the in vitro antiplasmodial activity of gossypol was also demonstrated; the IC50 value of ( R)- 1 was 4.5 +/- 0.2 microM, with the eudismic ratio of about 2.5. No gossypol was detected in Gossypioides kirkii.
ChemBioChem | 2007
Line Vedel; Gitte Bonke; Camilla Foged; Hanne L. Ziegler; Henrik Franzyk; Jerzy W. Jaroszewski; Christian A. Olsen
Malaria, especially the type caused by Plasmodium falciparum parasite strains, is a major tropical disease, estimated by the World Health Organization (WHO) to infect 300 to 500 million people per year, with a mortality rate of 1.1 to 2.7 million deaths per year. The advancement of resistance towards known drugs calls for the discovery of novel classes of antiparasitic compounds. Recently, the antiplasmodial activity of ACHTUNGTRENNUNGantimicrobial peptides of fungal and amphibian origin as well as of peptides from a phage-display library has been reported. Although some of these peptides contain nonproteinogenic amino acids, they are all a-peptides and are as such susceptible to proteolytic degradation. However, natural products that contain multiple N-methylated amino-acid residues have also been shown to have antiplasmodial activity. 6] Hence, we found it would be interesting to test whether the recently ACHTUNGTRENNUNGreported antimicrobial a-peptide–b-peptoid chimeras would display antiparasitic activity. Novel peptidomimetic backbone designs are of interest as a means of expanding the diversity of biomimetic polymers with respect to folding and biological properties. The chimeric a-peptide–b-peptoid constructs (Scheme 1), which have been found to possess antimicrobial activity without lysing human red blood cells in the active concentration range, are resistant against proteolysis. These chimeras are readily assembled by solid-phase peptide synthesis protocols by using building blocks that are efficiently prepared on the gram scale. 10] Here, we describe the discovery of promising biomimetic antiplasmodial oligomers with this backbone as well as the profiling of their membrane activity. The molecular design chosen here is based on alternating repeats of N-alkylated b-alanine (b-peptoid) units and aamino acids. The rationale behind this design was to gain structure-promoting effects and lipophilicity from the unnatural chiral b-peptoid residues (for circular dichroism studies, see refs. [7] , [11], and [12]), while the a-amino acids provide the side-chain functionality and intramolecular hydrogen bonding
Journal of Medicinal Chemistry | 2010
Sidsel Frølund; Angelo Bella; Anders Kristensen; Hanne L. Ziegler; Matthias Witt; Christian A. Olsen; Kristian Strømgaard; Henrik Franzyk; Jerzy W. Jaroszewski
An array of analogues of the wasp toxin philanthotoxin-433, in which the asymmetric polyamine moiety was exchanged for spermine and the headgroup replaced with a variety of structurally diverse moieties, was prepared using parallel solid-phase synthesis approaches. In three analogues, the spermine moiety was extended with an amino acid tail, six compounds contained an N-acylated cyclohexylalanine, and four analogues were based on a novel diamino acid design with systematically changed spacer length between N-cyclohexylcarbonyl and N-phenylacetyl substituents. The analogues were studied using two-electrode voltage-clamp electrophysiology employing Xenopus laevis oocytes expressing GluA1(i) AMPA or GluN1/2A NMDA receptors. Several of the analogues showed significantly increased inhibition of the GluN1/2A NMDA receptor. Thus, an analogue containing N-(1-naphtyl)acetyl group showed an IC(50) value of 47 nM. For the diamino acid-based analogues, the optimal spacer length between two N-acyl groups was determined, resulting in an analogue with an IC(50) value of 106 nM.
Bioorganic & Medicinal Chemistry | 2004
Hanne L. Ziegler; Henrik Franzyk; Majid Sairafianpour; Mehrnoush Tabatabai; Mahboubeh D Tehrani; Karim Bagherzadeh; Henry Hägerstrand; Dan Staerk; Jerzy W. Jaroszewski
Journal of Natural Products | 2004
Javad Asili; Maja Lambert; Hanne L. Ziegler; Dan Staerk; Majid Sairafianpour; Matthias Witt; Gholamreza Asghari; Ismaiel S. Ibrahimi; Jerzy W. Jaroszewski
Planta Medica | 2002
Hanne L. Ziegler; Thomas Høgh Jensen; Jette Christensen; Dan Staerk; Henry Hägerstrand; Archibald Sittie; Carl Erik Olsen; Trine Staalsø; Patrick Ekpe; Jerzy W. Jaroszewski
Planta Medica | 2003
Majid Sairafianpour; Babak Bahreininejad; Matthias Witt; Hanne L. Ziegler; Jerzy W. Jaroszewski; Dan Staerk