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FRINATEK-Fri prosj.st. mat.,naturv.,tek

HIT-TO-LEAD DEVELOPMENT OF NOVEL ANTIMICROBIAL AND ANTICANCER PEPTIDOMIMETICS

Awarded: NOK 3.4 mill.

The NFR/UiT-Fellesløft financed project - Hit-to-lead development of novel antimicrobial and anticancer peptidomimetics - is based on synthesis and bioactivity screening of small beta2,2-amino acid derivatives (3-amino-2,2-disubstituerte propansyrer) that show high potency against several pathogenic bacteria, biofilm and cancer cells. By project manager: Professor Morten Bøhmer Strøm (UiT - The Arctic University of Norway). September 2015. During the recent project period one of the beta2,2-amino acid derivatives that have been developed in the project has been selected for pre-clinical evaluation against cancer in collaboration with the pharmaceutical company Lytix Biopharma. PhD student Marianne Hagensen Paulsen has furthermore completed the development of a new synthetic route for synthesis of halogenated beta2,2-amino acid derivatives in collaboration with Associate Professor Annette Bayer and Researcher PhD Magnus Engqvist (UiT - The Arctic University of Norway). The synthesised compounds have been screened against clinical bacterial isolates from the University Hospital of North Norway (UNN) in collaboration with Professor Johanna U. Ericson Sollid (UiT - The Arctic University of Norway), and have shown high antimicrobial activity against 30 multiresistant bacterial strains. The investigations included five isolates of each of the resistant bacterial strains Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa og Escherichia coli. PhD student Marianne Hagensen Paulsen has in accordance with the project description also developed a synthetic route for a new class of potential bioactive compounds fulfilling our pharmacophore model, and by combining structural elements from isolated marine compounds from the arctic and sub-arctic regions with our beta2,2-amino acid derivatives. Synthesis of analogs is on going for further structure-activity relationship studies. The project group has recently initiated a collaboration with the research group of Associate Professor Christian Hedberg (Umeå university, Kemiska institutionen, Sweden) involving synthesis of linear and cyclic peptidomimetics with the halogenated beta2,2-amino acid derivatives incorporated as lipophilic building blocks. An objective of the project is to prepare peptidomimetics with activity against Gram-negative bacteria, such as E. coli and P. aeruginosa, and also to screen against other clinical isolates available at Umeå University. PhD student Marianne Hagensen Paulsen is therefore visiting Hedbergs group for six months during the autumn of 2015, and working on synthesis and bioactivity screenings. Post doctor Dominik Ausbacher has during two consecutive visits to the University of Helsinki (UH, Finland), and Center for Biofilm Engineering, Montana State University (MSU) investigated the mode-of-action of selected beta2,2-amino acid derivatives. The studies were performed in collaboration with Adjunct Professor Adyary Fallarero (UH), Assistant Professor Darla Goeres (MSU) and Professor Phil Stewart (MSU). The results revealed that the selected beta2,2-amino acid derivatives accumulated both in the bacteria and the biofilm matrix, and the treatment resulted in bactericidal effects together with degradation of the bacterial biofilm. The effect was quick and could be followed in real-time by fluorescence marked bacteria and confocal laser scanning microscopy (CLSM). We have during the recent project period also turned our interest towards development of potential formulations for administration of active beta2,2-amino acid derivatives. Masterstudent Josef Azumah has in collaboration with Post doctor Dominik Ausbacher and Professor Natasa Skalko-Basnet (UiT - The Arctic University of Norway) studied incorporation of beta2,2-amino acid derivatives into liposomes. Even though membrane disrupting effects have been observed, the study showed that we were able to incorporate the beta2,2-amino acid derivatives into liposomes. The results are thereby promising with respect to more advanced studies of such formulations in the future, i.e. using beta2,2-amino acid derivatives incorporated into liposomes for treatment of topical bacterial infections and for chronic wound healing.

During the last two decades only four new antimicrobial drugs have been approved for treatment of serious pathogenic infections. Meanwhile, bacterial resistance has become a major public concern, as exemplified by isolation of multiresistant Gram-negative enterobacteriaceae Escherichia coli and Klebsiella pneumoniae containing the New Dehli metallo-beta-lactamase 1 (NDM-1) gene. An extensively investigated class of anti-infective drug candidates is cationic antimicrobial peptides that have a unique mode o f action by targeting and rapidly destroying the bacterial cell membrane. However, due to inappropriate pharmacokinetic properties the majority of these drug candidates in clinical trials are directed towards treatment of bacterial skin infections. We hav e, however, developed a series of small sized beta-amino acid hit-compounds (molecular mass <500 Daltons) that are the first reported molecules resembling cationic antimicrobial peptides with potential for oral administration and systemic treatment of bac terial infections. The beta-amino acid hit-compounds are highly potent against methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE) and Escherichia coli, and show no or very low hemolytic activity. An exiting screening-study at the National Cancer Institute has also revealed that one of the beta-amino acid hit-compounds is almost 4-times more potent against 58 out of 59 different human cancer cell lines than the anticancer drug tamoxifen. In the curre nt project proposal we will continue the design, synthesis and pharmacological investigations of this new class of small antimicrobial and anticancer agents. By nature of their unique mode of action by disrupting the cell membrane of bacteria and cancer c ells, the novel beta-amino acid hit-compounds may evade the drug resistance mechanisms of bacteria and cancer cells, and thereby also be effective against multi-drug resistant cell lines.

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FRINATEK-Fri prosj.st. mat.,naturv.,tek