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Tuesday, June 6 • 11:30 - 12:50
Session 1

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Thomas Poulsen, Aarhus University:

Rakicidin A, a cyclic lipodepsipeptide (CLD) isolated from Micromonospora sp., exhibits selective cytotoxicity towards hypoxic cancer cells and induces apoptosis in quiescent imatinib-resistant stem-like CML cells. Hypoxic cancer cells display increased resistance to both chemo-and radiotherapy and hypoxia has been found to mediate cellular dedifferentiation in several cancer sub-types. BE-43547 is a structurally related natural product class that also displays potent anti-proliferative activity although its sub-selectivities towards hypoxic cancer cells had until recently not been elucidated. The macrocyclic systems of both rakicidin A and the BE-43547A-class constitute significant synthetic challenges due to the presence of congested structural elements and a labile 4-amido-2,4-pentadienoate (APD) functionality. The latter is unique to this family of natural products that we collectively refer to as APD-CLDs. In my presentation, I will present highlights form our recent efforts resulting in chemical syntheses of both rakicidin A[1] and the BE-43547A1-scaffold[2] and further provide a concise account of our studies aimed at elucidating the mode-of-action of these natural products.

 

Aurora Martinez Discovery of pharmacological chaperones for the correction of loss of function genetic disorders

 Small molecular weight compounds that selectively bind and stabilize mutant misfolded proteins may totally or partially recover the function and localization of the mutant proteins in the cell. These stabilizing compounds are called pharmacological chaperones and are the focus of increasing interest due to their therapeutic potential for correction of loss-of-function misfolding diseases. Phenylketonuria (PKU) is the most common inborn error of metabolism, caused by mutations in the gene encoding the enzyme phenylalanine hydroxylase (PAH), resulting in increased phenylalanine levels in blood and toxic levels in brain. The two current treatments of PKU, namely a strict phenylalanine diet and the administration of Kuvan®, are unsatisfactory since they are associated with neurodevelopmental or psychosocial problems and low responsiveness, respectively, and new therapeutic strategies are needed. In PKU, the majority of the (>900) mutations in PAH lead to a decrease in protein stability, and PKU is considered a paradigm of loss-of-function misfolding diseases. We thus initiated the screening and validation of compounds searching for stabilizers of PAH that can be developed into pharmacological chaperones for PKU treatment. The screening consisted of a sequential workflow comprising an initial high-throughput screening (HTS) of a 10,000-compound diversity library by differential scanning fluorimetry, a validation of the binding through surface plasmon resonance and activity assays, and an efficacy assessment in cultured cells constitutively expressing PAH, both in terms of specific activity and amount of protein. Subsequently, a further characterization of the mode and thermodynamics of the binding was performed. From a total of 109 positive compounds in the HTS the validations lead to the selection of 2 compound hits that are at present being expanded and optimized in a hit-to-lead phase, where validations on cells expressing PKU mutants has also been included. The same screening and validation strategy has been successfully applied to the selection of hit compounds with potential to be developed into pharmacological chaperones for other genetic neurometabolic disorders, such as rare dopamine deficiencies. 

Johanna U. E. Sollid, Antibacterial marine natural product mimics for treatment of infections

Bacterial infections are still among the urgent global challenges. Antibiotic resistance is currently causing around 700 000 deaths annually, with an estimated rise to 10 million over the next 30 years. Continuous development of antimicrobial compounds with new modes of action is essential to reduce the threat posed by antimicrobial resistance. Compounds with novel structures and properties such as synthetic compounds, based on known natural antimicrobials are promising in this respect.

A library of Marine Natural Product Mimics (MNPMs) constructed using a bioactivity-guided synthesis approach, was assessed. The bioactivity test platform included a reference panel of laboratory bacterial strains and an expanded panel of clinical isolates of human pathogens. A set of in vitro assays was applied to define the mode of action for selected molecules.

The aim was to identify antibacterial compounds by multistep screening of a synthetic MNPMs library and determine the mode of action of selected MNPMs.

Our strategy yielded several molecules with promising antibacterial activity. One example, E23 was active against clinical isolates of human pathogenic bacteria, including drug-resistant bacteria, in vitro. The primary killing mechanism of E23 is cytoplasmic membrane disruption. No resistance development towards E23 was revealed by serial passage experiments.

 

 

 

 

 

 

 

 


Moderators
avatar for Jeanette Andersen

Jeanette Andersen

Research Manager, UiT-The Arctic University of Norway
Jeanette Hammer Andersen (PhD) is head of Marbio, an analytical platform for natural product drug discovery at UiT- The Arctic University of Norway. Marbio has experience in screening extract library of natural product origin, both terrestrial and marine organisms and has successfully identified several novel bioactive compounds in marine natural products libraries. Main research interests are: marine biodiscovery, natural products, bioassays and high throughput screening technology. Industry collaboration through MabCent-SFI a centre for research based innovation centre for marine bioactives and drug discovery since 2007. Partner and work package leader in the EU FP7 project PharmaSea- Increasing Value and Flow in the Marine Biodiscovery Pipeline (2012-2016). MABIT board member since 2009. The MABIT-programme is an industrial... Read More →

Speakers
avatar for Aurora Martinez

Aurora Martinez

Professor Department of Biomedicine, University of Bergen
avatar for Thomas Poulsen

Thomas Poulsen

Assistant Professor, Aarhus University, Department of Chemistry
Thomas B. Poulsen is an assistant professor at the Dept. of Chemistry, Aarhus University in Denmark. Thomas completed his PhD with Prof. Karl Anker Jørgensen in 2008 working on the development of a series of new asymmetric organocatalytic transformations. He then moved to Harvard University as a post-doctoral fellow with Prof. Matthew D. Shair at the Department of Chemistry and Chemical Biology, where he worked on target-identification studies of complex anti-cancer natural products. From 2011, Thomas was an independent researcher at the Dept. of Chemistry, Aarhus University supported by an elite junior scientist programme (Sapere Aude) from the Danish Research Council and since 2012 he has been an assistant professor at the same institution... Read More →
avatar for Johanna Sollid

Johanna Sollid

Professor in Microbiology, UiT The Arctic University of Norway
I am Johanna Sollid, born in 1962. I have a PhD in microbiology (1990) from the University of Umeå, Sweden. I was a post doc at UiT the Arctic University of Norway in Tromsø until appointed Associate professor in 1992. Since 2005, I am Professor in microbiology at the same University. My main research interests are determinants for bacterial colonisation and new antimicrobial strategies. I have 45 peer-reviewed scientific publications, 31 the last ten years, and my H-index is 24. I have supervised numerous postdocs, PhDs and MSc candidates. Presently I am the co-director of the national PhD school... Read More →


Tuesday June 6, 2017 11:30 - 12:50
Auditorium 4