Peptide-based Drug Research
Epitope mapping of proteins related to autoimmune diseases is carried out in collaboration with Gunnar Houen (Prof. SSI/Southern University of Denmark). The project involves 1 PhD student (co-supervisor: PRH), 2 MSc students and 2 bachelor students.
The cause of autoimmune diseases is unknown, but one hypothesis is molecular mimicry where a foreign antigen shares sequence or structural similarities with self-antigens. The aim is to use autoantibodies from selected autoimmune diseases to identify which protein regions they recognize. This is performed by synthesizing overlapping peptides covering the entire protein.
In collaboration with Andreas Kjær (Prof., Dept. of Nuclear Medicine, Copenhagen University Hospital) we aim to develop peptide-based PET-ligands for the cancer specific receptor EGFRvIII. Positron Emission Tomography is an imaging method used for diagnostics, staging and treatment monitoring of cancer. Presently only non-specific tracers are known. Thus, development of a true cancer-specific tumour-targeting ligand for PET is of great clinical importance. A PET-tracer for diagnostic imaging of cancer patients will be developed in a PhD project (co-supervisor: PRH) funded by Copenhagen University Hospital.
Design and synthesis of novel peptide analogues and amino acids
Development of novel solid-phase organic chemistry and its application in medicinal chemistry studies of biologically active analogues comprise
(i) utilization of aziridines in solid-phase synthesis (SPS) of unnatural amino acid building blocks, and
(ii) design and synthesis of peptidomimetics displaying novel peptidomimetic backbones.
Efficient uptake of drugs is often just as essential as high potency of the drug itself – it may even be a prerequisite for the implementation of novel therapies. Thus, investigations aimed at peptide-assisted drug transport constitute an important contribution to research concerning delivery of advanced types of medicine.
Studies towards improved cell-penetrating peptides and cationic dendrimers for macromolecular drug delivery are performed in cooperation with Department of Pharmacy (HMN) and Dept. of Cellular and Molecular Medicine.
Bacterial genomes differ significantly from the human genome, and hence expression of essential genes may be inhibited by PNA-DNA antisense interference leading to the killing of the bacteria. However, more effective delivery peptides are required, and the concept of antibacterial antisense therapy based on AMP-PNA conjugates is investigated in a joint PhD project (HF and Peter E. Nielsen, Prof., Dept. of Cellular and Molecular Medicine).
Bacteria possessing genes for ESBL ("Extended Spectrum Beta-Lactamases") are resistant to penicillins, and they are reported still more frequently. Normally, the mortality of sepsis is 20%, but increases 2- to 3-fold for infections involving ESBL bacteria. Moreover, ESBL genes are located on a plasmid often associated with resistance towards aminoglycosides and fluoroquinolones – in this case carbapenems constitute the only treatment left. However, strains also resistant to this antibiotic have emerged, and the resulting infections cannot be treated without severe side effects, and soon incurable infections may spread via hospitals. Unfortunately, discovery of novel classes of antibiotics has low priority in the pharmaceutical industry.
Partnership in the Danish Centre for Antibiotic Research and Development (DanCARD), granted by the Danish Council for Strategic Research, allows for further investigations of analogues of AMPs.
One project (HF) focuses on peptidomimetics, and for the first time several types of backbone designs, displaying the same sequence of side chains, are compared. High potency towards multidrug-resistant (MDR) strains of E. coli has been found for some analogues. Also, significant differences between subtypes regarding their haemolytic and cytotoxic properties have been observed.
In another project (PRH) the aim is to develop new peptide-based antibiotics which show selectivity towards Gram-negative bacteria. So far 42 analogues of the antibacterial decapeptide anoplin have been synthesized, and some analogues which display selectivity and activity against Gram-negative bacteria have been identified.
Both projects are collaborations with Niels Frimodt-Møller (Prof., Hvidovre Hospital/SSI) with respect to the microbiological evaluation and animal testing in a mouse model. Furthermore, the 3D structures of peptides and peptidomimetics in the presence of membrane models are investigated by NMR spectroscopy in collaboration with Reinhard Wimmer (Assoc. Prof., University of Aalborg).
In addition, there is collaboration (HF) with the group of Hanne M. Nielsen (HMN) regarding investigation of non-toxic cell-penetrating peptides (CPPs) with antibacterial activity as well as AMPs with cell-penetrating properties with the long-term aim of developing a novel treatment for intracellular bacterial infections (co-supervision of two PhD projects under DanCARD).
The majority of natural AMPs are linear peptides that are prone to proteolytic degradation. This may be circumvented by cyclization, and a few potent cyclic peptide antibiotics are known, including Polymyxin B and Gramicidin S. Using combinatorial libraries, we aim to identify new cyclic AMPs for treatment of multidrug-resistant (MDR) bacteria that cause infections in the hospital and in the community. This project started October 2012 and involves 1 PhD student (supervised by PRH) funded by the EU-ITN “TRAIN-ASAP”.
In collaboration with Luca Guardabassi (Prof., Dept. of Veterinary Disease Biology) we aim to develop novel antimicrobial peptide-peptoid hybrids for veterinary use. Skin infections caused by Methicillin resistant S. pseudintermedius are common in dogs and cats. This project started October 2012 and involves 1 PhD student (supervised by PRH) funded by the EU-ITN “TRAIN-ASAP”.
Partnership in the project ”Unique IPN technology prevents resistance” (financed by the Advanced Technology Foundation) concerns antibacterial materials for medical devices (joint with Dept. Pharmacy, Biomodics and Novozymes A/S). In this project an antibacterial silicone-based material for medical catheters and similar devices is under development (HMN, HF, Biomodics, Novozymes, and Hans-Jørn Kolmos, Prof., Odense University Hospital).
In collaboration with Birgitte Regenberg (BR; Assoc. Prof., Dept. of Biology, University of Copenhagen) antimicrobial peptides against fungal infections are investigated (HF and BR).
In the EPI-Expose therapeutic vaccine platform project, we aim to develop efficient therapeutic vaccine formulations against tuberculosis, hepatitis C virus and Prostate Cancer.
Our approach is based upon responses to target epitopes that are not recognised during the natural disease, so-called subdominant epitopes. The project is a collaboration with Professor Peter Andersen (Project leader), Dr. Else-Marie Agger SSI, Dr. Per Thor Straten (Herlev Hospital), Professor Jens Bukh (Hvidovre Hospital). The Project is funded by The Danish National Advanced Technology Foundation.
Collaborators - Antimicrobial compounds
Prof. Niels Frimodt-Møller, Rigshospitalet
Prof. Lone Gram, DTU-FOOD
Prof. Hans Jørn Kolmos, OUH
Assoc. Prof. Reinhard Wimmer, Aalborg Universitet
Prof. Peter E. Nielsen, SUND, KU
Prof. Peter Thulstrup, SUND, KU
Prof. Luca Guardabassi, SUND, KU
Prof. Hanne Ingmer, SUND, KU