Loading…
This event has ended. View the official site or create your own event → Check it out
This event has ended. Create your own
View analytic
Tuesday, June 6 • 16:30 - 18:00
Session 2

Sign up or log in to save this to your schedule and see who's attending!

Mikael Elofsson - Exploring the chemistry and biology of benzofuran based natural products: Identification of novel antibacterial agents

Antibiotics are viewed as one the most important factors contributing to human health and prosperity. However, the indiscriminate use of antibiotics has led to the emergence of multi-resistant “superbugs” e.g. the gram-negative pathogen Pseudomonas aeruginosa that resist many antibiotic treatments including combination therapies. Our ability to prevent and treat infectious diseases is today severely threatened and the need for new antibacterial therapies is evident. Many clinically relevant gram-negative pathogens e.g. Salmonella spp., Chlamydia spp., Shigella spp., Pseudomonas spp. and Yersinia spp. use a conserved syringe-like machinery called the type III secretion (T3S) system to inject toxins into the cytosol of host cells. The toxins block host cell functions and thereby create a niche that allows bacterial growth. The T3S system is essential for pathogens to evade the host immune defense and agents that inhibit the system will attenuate virulence without directly affecting growth of the pathogen. This chemical attenuation could enable the host to clear the infection and we hypothesize that the selective pressure for resistance will be significantly lower than for conventional antibiotics.
Recently, we have employed phenotypic screening to discover (-)-hopeaphenol, a resveratrol tetramer, as an irreversible and selective inhibitor of T3S in Y. pseudotuberculosis and P. aeruginosa [1, 2]. The chemistry of resveratrol oligomers is however challenging and their syntheses generally require multistep procedures [3]. To further explore the chemistry and biology of resveratrol based natural products we have ongoing projects covering total synthesis or resveratrol dimers and development of synthetic methodology [4, 5], diversity-oriented synthesis as well as design, synthesis and applications of fluorescent probes and affinity reagents for target identification. 

Morten Jorgensen - PDE2 Inhibitors: Novel therapies for CNS-disorders ? Medicinal chemistry highlights from a drug discovery project

The discovery of two screening hits from high-throughput screening and two different lead optimization strategies will be presented. The hit-to-lead campaign for the first hit was performed in a ‘classic’ potency-centric sense with an extensive Med.Chem program while the second hit series was optimized using structure-based drug design with an emphasis on Ligand Lipophilicity Efficiency.1 The consideration of physico-chemical properties lead to a compound series with a much improved overall profile as compared to the results obtained using the original strategy.The superior profile of the 2nd generation of compounds was evident when cosidering Lipiniski’s Rule-of-Five2 and when looking at the location of the compounds in a plot of MW vslogD (the so-called Golden Triangle analysis).3 The lessons learned in this and many other projects were instrumental in a fundamental change to the company’s compound acquisition and screening strategies that will be presented as a poster at this conference.4

 

[1] PD Leeson, B Springthorpe Nature Rev. Drug Discov. 20076, 881.

[2] CA Lipinski et al. Adv. Drug. Deliv. Rev. 199723, 3.

[3] DW Johnson, KR Dress, M Edwards Bioorg. Med. Chem. Lett. 200919, 5560.

[4] M Marigo, AG Sams, M Langård, L David, M Jørgensen ’Methods for Clean-up and Enrichment of Coporate Screening Collections’



Thierry Kogej - Screening collection enhancement through open-innovation

High-throughput screening (HTS) is one of the main tool for finding hits for drug discovery projects. The success of a HTS campaign relies on the wealth of the screening collection. Different open innovation strategies followed at AstraZeneca to ensure a continuous enrichment of the corporate collection will be presented.

Dr. Päivi Tammela Bioreporters in screening and characterization of novel antimicrobial agents against Gram-negative bacteria

According to a recent report by the WHO, a post-antibiotic era is a very real possibility for the 21st century. Antimicrobial resistance (AMR) has reached such alarming levels that available treatment options for common infections and minor injuries are becoming ineffective unless global actions across several sectors are taken. However, no first-in-class antibiotics against Gram-negative bacteria (GNB) have been developed for more than 40 years. Very worryingly, the emergence of E. coli carrying a new gene, MCR-1, providing resistance to colistin (the last resort antibiotic to treat multiple drug-resistant E. coli infections) has recently been reported and accentuates the urgent need for novel antimicrobials especially against GNB. To respond to this need, we have recently developed cell-based screening strategies for antimicrobial drug discovery by using E. coli bioreporter strains cloned with lux genes. These bioreporter-based assays are sensitive, allow automation, completion of assays in couple of hours, and monitoring of antimicrobial action of compounds in whole-cell context. We have demonstrated the functionality of this approach with screening of compound libraries, but also in studying natural product extracts. In summary, our results demonstrate that bioreporters are powerful tools both in HTS as well as in follow-up characterisation of novel antimicrobial agents. 

 


Moderators
avatar for Thomas Lundbäck

Thomas Lundbäck

Associate Director - Mechanistic Biology & Profiling, AstraZeneca
Thomas Lundbäck is Associate Director within the global Discovery Sciences organisation at AstraZeneca, providing reagent, assay development and screening services. Dr. Lundbäck also serves as an affiliate of the Karolinska Institutet, supporting the national chemical biology i... Read More →

Speakers
avatar for Mikael Elofsson

Mikael Elofsson

Umeå University
In 1996 Mikael Elofsson obtained his Ph.D. in in synthetic organic chemistry at the Lund Institute of Technology, Lund, Sweden. In the lab of Prof. Jan Kihlberg he worked with synthesis of glycosylated amino acids and their application in solid-phase synthesis of MHC class II binding glycopeptides. Thereafter he spent three years as postdoc in the lab of Prof. Craig M. Crews at Yale University, CT, USA working primarily on epoxyketone proteasome inhibitors. The work eventually led to the drug Kyprolis (Carfilzomib) that was approved by FDA in 2012. In 1999 Mikael was recruited to the Department of Chemistry at... Read More →
avatar for Morten Jørgensen

Morten Jørgensen

Discovery Chemistry and DMPK, Neuroscience Drug Discovery, H. Lundbeck
Dr. Morten Jørgensen has been working as a medicinal chemist at H. Lundbeck A/S for 14 years. Morten received his  PhD in  carbohydrate and organometallic chemistry from the Technical University of Denmark under the supervision of Professor Robert Madsen. Since then he has been working at H. Lundbeck A/S on a range of drug discovery projects within depression and anxiety... Read More →
avatar for Thierry Kogej

Thierry Kogej

Associate Principal Scientist, AstraZeneca
Thierry Kogej obtained his Ph.D in Physical-Chemistry at the University of Mons-Hainaut in Belgium in 1998. Worked at UCB Pharma as a medicinal computational chemist to support discovery projects in CNS and rhino-inflammatory (1998-2003). Got a Master in Drug Design at University of Lille (France) in 2000. Joined AstraZeneca... Read More →
avatar for Päivi Tammela

Päivi Tammela

Academy Research Fellow, Adjunct professor, University of Helsinki
Päivi Tammela received her Ph.D. in Pharmacy in 2004 (University of Helsinki, Finland). She has served as University Lecturer in Pharmaceutical Biology (2005-2007) at the University of Helsinki; and obtained Adjunct Professorship in Pharmaceutical Biology in 2005. Since 2008, she has served as University Researcher and Group Leader at the Faculty of Pharmacy where she currently leads the Bioactivity Screening Group. In 2011, Dr. Tammela completed a research visit at the University of Cambridge, UK. Currently, she holds the Academy of Finland Research Fellow position (2014-2019). Dr. Tammela has authored more than 60 peer-reviewed publications and 7 patents/patent applications. Tammela has received awards from the American Society of Pharmacognosy Foundation (Jack L. Beal Award, 2009) and from the Finnish Pharmaceutical Society (Albert Wuokko Award, 2006). Dr. Tammela actively participates in... Read More →


Tuesday June 6, 2017 16:30 - 18:00
Auditorium 4