Biomedical subjects

Håvard Jenssen

Publications and source records attributed to Håvard Jenssen.

9 recordsLinked to original sources

PubMed2006

Prediction of activity, synthesis and biological testing of anti-HSV active peptides.

Herpes simplex virus infections can be treated with a number of drugs, but as for all pathogens, there is a constant need for new therapies. In the search for lead compounds some peptides have proven to possess an antiviral effect, but it is still unclear what mechanisms are responsible for this effect. We wish to report on the use of principal properties of amino acids for developing quantitative structure-activity relationships (QSAR:s) as a tool for modelling peptide activity and predicting the activity of new peptides. In order to test the reliability of the method, new peptides have been designed by using multivariate methodology, synthesized and tested for a number of responses. Two of the new peptides synthesized were active at lower concentrations than experienced before regarding entry and herpes simplex virus activity, but they were not able to completely inhibit viral infection. This may reflect differences in mode of action of peptides depending on the amino acid content.

Amino Acid Sequence↗

PubMed2006

Peptide antimicrobial agents.

Antimicrobial host defense peptides are produced by all complex organisms as well as some microbes and have diverse and complex antimicrobial activities. Collectively these peptides demonstrate a broad range of antiviral and antibacterial activities and modes of action, and it is important to distinguish between direct microbicidal and indirect activities against such pathogens. The structural requirements of peptides for antiviral and antibacterial activities are evaluated in light of the diverse set of primary and secondary structures described for host defense peptides. Peptides with antifungal and antiparasitic activities are discussed in less detail, although the broad-spectrum activities of such peptides indicate that they are important host defense molecules. Knowledge regarding the relationship between peptide structure and function as well as their mechanism of action is being applied in the design of antimicrobial peptide variants as potential novel therapeutic agents.

Amino Acid Sequence↗

PubMed2005

Induced resistance to the antimicrobial peptide lactoferricin B in Staphylococcus aureus.

This study was designed to investigate inducible intrinsic resistance against lactoferricin B in Staphylococcus aureus. Serial passage of seven S. aureus strains in medium with increasing concentrations of peptide resulted in an induced resistance at various levels in all strains. The induced resistance was unstable and decreased relatively rapidly during passages in peptide free medium but the minimum inhibitory concentration remained elevated after thirty passages. Cross-resistance to penicillin G and low-level cross-resistance to the antimicrobial peptides indolicidin and Ala(8,13,18)-magainin-II amide [corrected] was observed. No cross-resistance was observed to the human cathelicidin LL-37. In conclusion, this study shows that S. aureus has intrinsic resistance mechanisms against antimicrobial peptides that can be induced upon exposure, and that this may confer low-level cross-resistance to other antimicrobial peptides.

Anti-Bacterial Agents↗

PubMed2005

Modelling of anti-HSV activity of lactoferricin analogues using amino acid descriptors.

Herpes simplex virus (HSV) causes a number of diseases and new therapies are being pursued vigorously. Earlier studies have shown that modified peptides based on lactoferricins reduce HSV-1 and HSV-2 infection, and structure-activity studies indicate that the anti-viral activity correlates with the binding affinity for heparan sulphate and chondroitin sulphate. In this study it is shown that theoretically derived amino acid descriptors can be used to model the anti-viral activity of peptides, as well as other peptide properties, even more accurately.

Amino Acids↗

PubMed2005

Human lactoferricin is partially folded in aqueous solution and is better stabilized in a membrane mimetic solvent.

Lactoferricins are highly basic bioactive peptides that are released in the stomach through proteolytic cleavage of various lactoferrin proteins. Here we have determined the solution structure of human lactoferricin (LfcinH) by conventional two-dimensional nuclear magnetic resonance methods in both aqueous solution and a membrane mimetic solvent. Unlike the 25-residue bovine lactoferricin (LfcinB), which adopts a somewhat distorted antiparallel beta sheet, the longer LfcinH peptide shows a helical content from Gln14 to Lys29 in the membrane mimetic solvent but a nonexistent beta-sheet character in either the N- or C-terminal regions of the peptide. The helical characteristic of the LfcinH peptide resembles the conformation that this region adopts in the crystal structure of the intact protein. The LfcinH structure determined in aqueous solution displays a nascent helix in the form of a coiled conformation in the region from Gln14 to Lys29. Numerous hydrophobic interactions create the basis for the better-defined overall structure observed in the membrane mimetic solvent. The 49-residue LfcinH peptide isolated for these studies was found to be slightly longer than previously reported peptide preparations and was found to have an intact peptide bond between residues Ala11 and Val12. The distinct solution structures of LfcinH and LfcinB represent a novel difference in the physical properties of these two peptides, which contributes to their unique physiological activities.

Amino Acid Sequence↗

PubMed2004

Anti-HSV activity of lactoferrin and lactoferricin is dependent on the presence of heparan sulphate at the cell surface.

Lactoferrin (LF) is a multifunctional glycoprotein, which plays an important role in immune regulation and defense mechanisms against bacteria, fungi, and viruses. Lactoferricin (Lfcin) is a potent antimicrobial peptide generated from the N-terminal part of LF by pepsin cleavage. In this study, we investigated the mechanisms of the anti-herpes simplex virus (anti-HSV) activity of LF and Lfcin. The results demonstrated that LF and Lfcin inhibited the entry of HSV into Vero cells. LF had no effect against HSV after the virus had entered the cells, while Lfcin exerted antiviral activity also after the initial binding of the virus to the host cell. The distribution of LF and Lfcin in the cells was investigated by immunogold-labeling and transmission electron microscope (TEM). LF was found mainly at the cell surface in cells expressing heparan sulphate. Lfcin was randomly distributed intracellularly. LF must be present at the cell surface to exert antiviral activity, while Lfcin exert its antiviral activity also when found mainly intracellularly. Both LF and Lfcin were dependent on the presence of heparan sulphate at the cell surface to exert their antiviral activity.

Animals↗

PubMed2004

Anti-HSV activity of lactoferricin analogues is only partly related to their affinity for heparan sulfate.

Earlier studies have shown that the heparan sulfate (HS) on the cell surface acts as a receptor for herpes simplex virus (HSV). We have recently shown that bovine lactoferricin (LfcinB), a small part of the milk protein lactoferrin, inhibits HSV-1 and HSV-2 infection, probably by blocking the entry of the virus. The human homologue (18-42), which shares 36% sequence similarity with LfcinB (17-41), displayed much lower antiviral activity. In the present study, a set of cyclic and linear human and bovine Lfcin derivatives were constructed to investigate the relation between their affinity to HS and chondroitin sulfate (CS) and their antiviral activity against HSV-1 and HSV-2. The lactoferrin (LF) proteins and several of the Lfcin derivatives exhibited similar affinity for HS, but the LF proteins possess a much higher antiviral activity than the smaller peptides. Our structure-activity relationship studies on the Lfcin derivates confirmed that affinity for HS, that was correlated to the net positive charge, is an important factor, but does not well predict the antiviral activity. Structural parameters such as hydrophobicity, molecular size, spatial distribution of charged and lipophilic amino acids, and the cyclic structure of Lfcin also seem to be important factors to govern antiviral activity against HSV.

Amino Acid Sequence↗

PubMed2004

A wide range of medium-sized, highly cationic, alpha-helical peptides show antiviral activity against herpes simplex virus.

Ten highly cationic, alpha-helical peptides were synthesized and tested for antiviral activity against herpes simplex virus 1 and 2 (HSV-1 and HSV-2). Several of the peptides were found to exhibit antiviral activity. The peptides affinity for heparan sulfate (HS) increased with the number of cationic residues. Net charge could be decisive for the anti-HSV-1 activity, while secondary structure of the peptides seems more important for the anti-HSV-2 activity. The peptides were able to inhibit the entry of HSV-1 into the host cell, probably by blocking HS at the cell surface. HSV plaque formation was inhibited in a dose-dependent manner when cells were exposed to the peptides prior to the addition of virus. Lower inhibition activity was observed when the virus was allowed to attach to the cell surface before the addition of peptide. However, the plaque size was smaller compared to the untreated control, indicating that the peptides may also interfere with cell-to-cell spread of the virus. The two most potent antiviral peptides exhibited synergy with acyclovir against HSV.

Amino Acid Sequence↗

PubMed2003

Lactoferrin and lactoferricin inhibit Herpes simplex 1 and 2 infection and exhibit synergy when combined with acyclovir.

Lactoferrin (LF) is a multifunctional glycoprotein, which plays an important role in immune regulation and defense mechanisms against bacteria, fungi, and viruses. Upon peptic digestion of LF, a peptide called lactoferricin (Lfcin) is generated. Lfcin corresponds to the N-terminal part of the protein. In this study we investigated the antiviral activity of bovine and human Lfcin against Herpes simplex virus (HSV)-1 and HSV-2. The 50% effective concentrations (EC(50)) for LF and Lfcin against several clinical isolates of HSV-1 and HSV-2, including acyclovir (ACV)-resistant strains, were determined. We further evaluated the effect of the combination of either LF or Lfcin with ACV against HSV-1 and HSV-2. Synergy was observed between both LF or Lfcin in combination with ACV against the HSV laboratory strains. The 50% effective concentration (EC(50)) for ACV and LF or Lfcin, when combined with ACV, could be reduced by two- to sevenfold compared to the EC(50) when the drugs were used alone.

Acyclovir↗