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Institut Pasteur Korea is an infectious-disease focused research institute that utilizes proprietary platforms to identify novel molecular targets and discover small molecules to diagnose, treat and address serious, unmet global public health needs.
With the current lengthy multi-therapy and the emergence of drug resistant strains of M. tuberculosis, new approaches to target the tubercle bacillus are urgently needed. A critical feature of the bacillus is its ability to survive within macrophages, making these host cells an ideal niche for persisting microbes. Based on this particular feature, we developed a phenotypic cell-based assay that enables the search for drugs that interfere with the multiplication of M. tuberculosis within host macrophages. Based on the use of fluorescently labeled living macrophages infected with fluorescently labeled mycobacteria, this assay allows recording of the intracellular mycobacterial growth by automated confocal fluorescence microscopy. The effective compounds will further be developed for drug discovery purposes up to the preclinical phases.
Institut Pasteur Korea has devised strategies using the infectious hepatitis C virus (HCV) cell culture system and has carried out a phenotypic, target-free screening campaign. By excluding compounds active in the replicon system and including those active on HCV E1/E2 mediated entry, we focused on identifying inhibitors interfering with early and late steps of the HCV life cycle. Druggable hits were selected and further characterized in order to determine the mechanism of action (MoA), antiviral potency and to evaluate properties crucial for drug development.
In order to identify new inhibitors with a novel MoA, Institut Pasteur Korea partnered with Sanofi and Yonsei University and devised a hepatitis B virus (HBV) cell-based high throughput screening (HTS) assay and screened 110,000 small molecules to identify compounds targeting the interaction of the HBV polymerase (Pol) with the viral encapsidation signal epsilon (ε) located on viral pregenomic RNA (pgRNA). After hit confirmation, selected hits were characterized in cell culture systems.
To identify immunomodulators that restore innate immunity in chronically HBV-infected hepatocytes, Institut Pasteur Korea, in conjunction with Sanofi and Yonsei University, developed and screened 310,000 compounds using HTS and triaged hits to identify HBV-specific immunomodulators.
Furthermore, we are developing a state-of-the-art HTS assay with HBV-susceptible cell lines to screen for viral interventions targeting the entire viral life cycle. With this system, we intend to screen small molecule compounds, as well as natural compound libraries. Identified hits will be highly characterized, and inhibitors with novel MoA and drug-like properties will be subjected to early structure activity relationship (eSAR) studies.
Our proposed strategies will generate knowledge, as well as research tools, to facilitate screening for novel viral interventions which may open avenues to develop new strategies to fight chronic viral hepatitis.
The influenza drug discovery program at Institut Pasteur Korea was established in 2012. Currently, the main research objective is to develop new treatments for emerging and re-emerging strains of influenza viruses. To this end, we are utilizing target-free chemical genomics and target-based approaches to understand the host-pathogen relationship in an effort to simultaneously identify new targets and potential lead therapeutic compounds. Institut Pasteur Korea has the competence to manage and execute a drug discovery program. We have developed and optimized biological assays that have led to the discovery of new targets and compounds for influenza. In addition, continued efforts will be made to analyze interactions between these antiviral agents and viral and other specific cellular targets during virus infection. This research will address both the function and mechanism of action of the novel small molecule antiviral agents in the context of viral and/or cellular protein interactions, and its findings could advance the field of antiviral therapies against emerging and re-emerging influenza viruses that cause significantly high mortality and morbidity in human.
A small group of bacteria, referred to as the ‘ESKAPE’ bugs ― Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumanii, Pseudomonas aeruginosa and Enterobacter species ― is among the biggest infectious disease threat, causing more than 40% of infections in US hospitals.
The goal of this research is to apply the knowledge of bacterial physiology, including metabolism and mechanism of antibiotic resistance, to the development of new antibacterial approaches against superbugs. We target Pseudomonas aeruginosa and Staphylococcus aureus, two major causative agents of community and hospital acquired bacterial infections. As a first approach, we have developed an innovative physiological assay system for screening compounds active against P. aeruginosa in collaboration with clinical scientists and researchers from Yonsei University. Using this assay system, we successfully screened 200,000 compounds and identified several active compounds which have been a valuable tool to evaluate the essential pseudomonal metabolism. Based on our experience investigating P. aeruginosa metabolism, we will study antibacterial resistance mechanisms, especially focusing on efflux pumps in S. aureus. Our research will provide in-depth knowledge of bacterial physiology and potentially suggest new approaches to discover antibiotics.
The Leishmania research program focuses on discovery of novel inhibitors of Leishmania infection. The program is focused on two key areas: the discovery of novel lead compounds in collaboration with the screening technology and chemistry groups; and understanding the fundamental biology of Leishmania with a special emphasis on the mitochondria of the parasite known as kinetoplast.
Leishmania, in the family of Kinetoplastida, contains a unique organelle called a kinetoplast. Because this organelle is exclusive to Leishmania, it has been proposed as a promising target. However, limited understanding of the underlying biology has hindered the discovery of inhibitors targeting this specific organ. Our goal is to use a high throughput screening system to drive a lead compound discovery program, and at the same time utilize secondary assays developed at Institut Pasteur Korea to select compounds that target the kinetoplast to understand the underlying mechanism of the kinetoplast. At the interface of these two strategies, we ultimately aim to identify lead compounds that target the kinetoplast and evaluate their efficacy using an in vivo Leishmania infection mouse model for a proof of concept study. Using our expertise of molecular parasitology, biophysics and biochemistry, we will approach the target system from the parasite or organelle level, while at the same time analyzing the proteins that are involved in the kinetoplast machinery.
Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor and the second leading cause of cancer-related deaths in the world. To date, no single agent or combination therapy has demonstrated any advantage in terms of both overall survival and quality of life.
To address this unmet need, greater understanding of the cross-talk between tumor cells and their microenvironment, and the interactions between cancer cells and cancer stem-like cells, are needed to fully understand tumor development, progression and chemo-resistance in HCC. For this reason, Institut Pasteur Korea is focused on the development of a physiological relevant assay system using a 2D and/or 3D mixed-culture system to screen for inhibitors of tumorigenesis, as well as the elucidation of chemotherapy resistance mechanisms in liver cancer stem cells to define novel targets for liver cancer therapy.