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Dive into the research topics where Terkel Hansen is active.

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Featured researches published by Terkel Hansen.


Journal of Medicinal Chemistry | 2010

Antimicrobial Activity of Small β-Peptidomimetics Based on the Pharmacophore Model of Short Cationic Antimicrobial Peptides

Terkel Hansen; Tore Alst; Martina Havelkova; Morten B. Strøm

We have synthesized a series of small beta-peptidomimetics (M(w) <650) that were based on the minimal pharmacophore model for anti-Staphylococcal activity of short cationic antimicrobial peptides. All beta-peptidomimetics had a net charge of +2 and formed an amphipathic scaffold consisting of an achiral lipophilic beta(2,2)-amino acid coupled to a C-terminal l-arginine amide residue. By varying the lipophilic side-chains of the beta(2,2)-amino acids, we obtained a series of highly potent beta-peptidomimetics with high enzymatic stability against alpha-chymotrypsin and a general low toxicity against human erythrocytes. The most potent beta-peptidomimetics displayed minimal inhibitory concentrations of 2.1-7.2 muM against Staphylococcus aureus, methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and Escherichia coli. Small amphipathic beta-peptidomimetics may be a promising class of antimicrobial agents by means of having a similar range of potency and selectivity as larger cationic antimicrobial peptides in addition to improved enzymatic stability and lower costs of production.


Journal of Medicinal Chemistry | 2011

Synthesis of Cationic Antimicrobial β2,2-Amino Acid Derivatives with Potential for Oral Administration

Terkel Hansen; Dominik Ausbacher; Gøril Eide Flaten; Martina Havelkova; Morten B. Strøm

We have prepared a series of highly potent achiral cationic β(2,2)-amino acid derivatives that fulfill the Lipinskis rule of five and that contain the basic structural requirements of short cationic antimicrobial peptides. Highest antimicrobial potency was observed for one of the smallest β(2,2)-amino acid derivatives (M(w) 423.6) exhibiting a MIC of 3.8 μM against methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and Staphylococcus aureus, and 7.7 μM against Escherichia coli. The β(2,2)-amino acid derivatives were shown to have similar absorption properties as several commercially available drugs, and the results implied a resembling membrane disrupting mechanism of action as reported for much larger cationic antimicrobial peptides. By their high potency, nontoxicity, absorption properties, and ease of synthesis, the β(2,2)-amino acid derivatives demonstrate a way to modify a vastly investigated class of cationic antimicrobial peptides into small drug-like molecules with high commercial potential.


Biochimica et Biophysica Acta | 2012

Anticancer mechanisms of action of two small amphipathic β(2,2)-amino acid derivatives derived from antimicrobial peptides.

Dominik Ausbacher; Gunbjørg Svineng; Terkel Hansen; Morten B. Strøm

We have recently discovered that small antimicrobial β(2,2)-amino acid derivatives (Mw<500) also display activity against cancer cells. To explore their drug potential, we have presently investigated the mechanisms of action of two derivatives BAA-1 (IC(50) 8.1μg/ml) and BAA-2 (IC(50) 3.8μg/ml) on Ramos human Burkitts lymphoma cells. Studies using annexin-V-FITC/propidium iodide staining and flow cytometry revealed essential mechanistic differences, which was confirmed by screening for active caspases, investigation of mitochondrial membrane potential, and electron microscopy studies. Our results indicated that BAA-1 killed Ramos cells by destabilizing the cell membrane, whereas BAA-2 caused apoptosis by the mitochondrial-mediated pathway.


Journal of Pharmaceutical Sciences | 2013

New Applications of Phospholipid Vesicle-Based Permeation Assay: Permeation Model Mimicking Skin Barrier

André Engesland; Merete Skar; Terkel Hansen; Nataša Škalko-Basnet; Gøril Eide Flaten

The phospholipid vesicle-based permeation assay (PVPA), based on a tight barrier composed of liposomes mimicking cells, is providing an opportunity to predict passive drug permeability through biological membranes. Although it was originally developed to mimic the intestinal epithelia, this study focuses on its potential as a simple and affordable skin model for transdermal permeation of drug candidates and evaluation of various drugs and formulations at an early development stage. The changes induced in lipid composition of the lipid-based barriers to better mimic the in vivo stratum corneum lipid composition required optimization of liposomal properties and manufacturing conditions applied in barrier formation. The preparation conditions could be modified to prepare lipid-based barriers of different degrees of leakiness, potentially representing different degree of intact and compromised skin. The different PVPA models developed in this study appeared to be able to distinguish between drugs with different degrees of lipophilicity and penetration potential. Moreover, the PVPA can be produced in controlled and reproducible manner with different degree of leakiness. The model could therefore be applied in both pharmaceutical and cosmeceuticals manufacturing and also has the potential to provide deeper insight on safety of nanodelivery systems administered onto the skin.


Journal of Peptide Science | 2012

Synthesis of anticancer heptapeptides containing a unique lipophilic β2,2-amino acid building block

Veronika Tørfoss; Dominik Ausbacher; Cristiane de A. Cavalcanti-Jacobsen; Terkel Hansen; Bjørn-Olav Brandsdal; Martina Havelkova; Morten B. Strøm

We report a series of synthetic anticancer heptapeptides (H‐KKWβ2,2WKK‐NH2) containing eight different central lipophilic β2,2‐amino acid building blocks, which have demonstrated high efficiency when used as scaffolds in small cationic antimicrobial peptides and peptidomimetics. The most potent peptides in the present study had IC50 values of 9–23 µm against human Burkitts lymphoma and murine B‐cell lymphoma and were all nonhaemolytic (EC50 > 200 µm). The most promising peptide 10e also demonstrated low toxicity against human embryonic lung fibroblast cells and peripheral blood mononuclear cells and exceptional proteolytic stability. Copyright


Scandinavian Journal of Immunology | 2005

Increased Frequency of Antral CD4+ T and CD19+ B Cells in Patients with Helicobacter pylori‐Related Peptic Ulcer Disease

Rasmus Goll; Anne Husebekk; V. Isaksen; G. Kauric; Terkel Hansen; Jon Florholmen

Only a fraction of Helicobacter pylori (HP)‐infected individuals develop clinical disease. Recent research indicates that immunological mechanisms may be important for understanding the pathophysiology of HP infection. Differences in the individual cellular immune response may reflect the clinical diversity. The aim of the present study was to investigate the cellular immune response against HP in three clinically well‐defined patient groups: HP‐positive peptic ulcer, HP‐positive and HP‐negative gastritis. Biopsies from gastric mucosa were processed for analysis by flow cytometry and histology. The number of T lymphocytes (CD3+) was significantly higher in HP‐positive peptic ulcer (13.8%) than in HP‐positive nonulcer gastritis (6.3%). A nonsignificant increase for B lymphocytes (CD19+) was noted as well. Furthermore, a significant difference was seen in mucosal CD4/CD8 ratio between HP ulcer (2.4) and nonulcer HP gastritis (1.0) patients. Thus, B cells (CD19+) and T‐helper cells (CD4+) were dominant in gastric mucosa from peptic ulcer patients, and cytotoxic T cells (CD8+) were relatively dominant in gastric mucosa from nonulcer patients. In conclusion, distinct differences in the T‐cell subset distribution of mucosal lymphocytes were detected in patients with HP infection, strongly correlated with the presence or absence of peptic ulcer.


European Journal of Medicinal Chemistry | 2012

Anticancer activity of small amphipathic β2,2-amino acid derivatives

Terkel Hansen; Dominik Ausbacher; Zack G. Zachariassen; Trude Anderssen; Martina Havelkova; Morten B. Strøm

We report the anticancer activity from screening of a series of synthetic β(2,2)-amino acid derivatives that were prepared to confirm the pharmacophore model of short cationic antimicrobial peptides with high anti-Staphylococcal activity. The most potent derivatives against human Burkitts lymphoma (Ramos) cells displayed IC(50) values below 8 μM, and low toxicity against human red blood cells (EC(50) > 200 μM). A more than 5-fold preference for Ramos cancer cells compared to human lung fibroblasts (MRC-5 cells) was also obtained for the most promising β(2,2)-amino acid derivative 3-amino-N-(2-aminoethyl)-2,2-bis(naphthalen-2-ylmethyl)propanamide (5c). Screening of 5c at the National Cancer Institute (NCI, USA) confirmed its anticancer potency and revealed a very broad range of anticancer activity with IC(50) values of 0.32-3.89 μM against 59 different cancer cell lines. Highest potency was obtained against the colon cancer cell lines, a non-small cell lung cancer, a melanoma, and three leukemia cell lines included in the NCI screening panel. The reported β(2,2)-amino acid derivatives constitute a promising new class of anticancer agents based on their high anticancer potency, ease of synthesis, mode-of-action, and optimized pharmacokinetic properties compared to much larger antimicrobial peptides.


Proteomics | 2013

Adenylylation, MS, and proteomics--Introducing a "new" modification to bottom-up proteomics.

Terkel Hansen; Michael F. Albers; Christian Hedberg; Albert Sickmann

Although the addition of a 5′‐adenosine phosphodiester group to proteins, called adenylylation, has been known for decades, the possibility that adenylylation could be a molecular switch in cellular signaling pathways has emerged recently. The distinct mass shift upon adenylation of threonine or tyrosine residues renders it a good target for MS detection and identification; however, the fragmentation of adenylylated peptides derived from proteolytic digestion of adenylylated proteins has not yet been systematically investigated. Here, we demonstrate that adenylylated peptides show loss of parts of the adenosine monophosphate (AMP) upon different fragmentation techniques. As expected, causing the least fragmentation of the AMP group, electron transfer dissociation yields less complicated spectra. In contrast, CID and higher energy collision (HCD) fragmentation caused AMP to fragment, generating characteristic ions that could be utilized in the specific identification of adenylylated peptides. The characteristic ions and losses upon CID and higher energy collision fragmentation from the AMP group turned out to be highly dependent on which amino acid was adenylylated, with different reporter ions for adenylylated threonine and tyrosine. We also investigated how adenylylation is best incorporated into search engines, exemplified by Mascot and showed that it is possible to identify adenylylation by search engines.


Proteomics | 2017

Proteomics of hydrophobic samples: Fast, robust and low-cost workflows for clinical approaches.

Yvonne Pasing; Sayda Colnoe; Terkel Hansen

In a comparative study, we investigated the influence of nine sample preparation workflows and seven different lysis buffers for qualitative and quantitative analysis of the human adipose tissue proteome. Adipose tissue is not just a fat depot but also an endocrine organ, which cross‐talks with other tissue types and organs throughout the body, like liver, muscle, pancreas, and brain. Its secreted molecules have an influence on the nervous, immune, and vascular system, thus adipose tissue plays an important role in the regulation of whole‐body homeostasis. Proteomic analysis of adipose tissue is challenging due to the extremely high lipid content and a variety of different cell types included. We investigated the influence of different detergents to the lysis buffer and compared commonly used methods like protein precipitation and filter‐aided sample preparation (FASP) with workflows involving acid labile or precipitable surfactants. The results indicate that a sodium deoxycholate (SDC) based workflow had the highest efficiency and reproducibility for quantitative proteomic analysis. In total 2564 proteins from the adipose tissue of a single person were identified.


International Journal of Pharmaceutics | 2015

β-CD-dextran polymer for efficient sequestration of cholesterol from phospholipid bilayers: Mechanistic and safe-toxicity investigations.

Dominik Stelzl; Thorbjørn Terndrup Nielsen; Terkel Hansen; Massimiliano di Cagno

The aim of this work was to investigate the suitability of β-cyclodextrin-dextran (BCD-dextran) polymer as cholesterol sequestering agent in vitro. For this purpose, BCD-dextran-cholesterol complexation was studied by phase solubility studies as well as with a specifically designed in vitro model based on giant unilamellar vesicles (GUVs) to evaluate the ability of this polymer to sequestrate cholesterol from phospholipid bilayers. Cholesterol-sequestering ability of BCD-dextran was also investigated on different cell lines relevant for the hematopoietic system and results were correlated to cells toxicity. BCD-dextran polymer was capable of extracting significant amount of cholesterol from phospholipid bilayers and to a higher extent in comparison to available β-cyclodextrins (BCDs). The ability of BCD-dextran in sequestering cholesterol resulted also very high on cell lines relevant for the hematopoietic system. Moreover, BCD-dextran resulted less toxic on cell cultures due to higher selectivity in sequestering cholesterol in comparison to MBCD (that sequestrated also significant amounts of cholesteryl esters). In conclusion, BCD-dextran resulted an extremely efficient cholesterol-sequestering agent and BCD-dextran resulted more selective to cholesterol extraction in comparison to other BCDs (therefore of lower cytotoxicity). This phenomenon might play a key role to develop an efficient treatment for hypercholesterolemia based on cholesterol segregation.

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Yvonne Pasing

University Hospital of North Norway

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Rasmus Goll

University Hospital of North Norway

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