The ongoing COVID-19 pandemic illustrates how substantially emerging virus infections can devastate our daily lives. Being prepared to these global challenges is now far more important than ever in the human history. Zoonotic Virus Laboratory is trying to understand emerging virus infections and to develop control measures such as small molecule inhibitors and therapeutic antibodies. Our expertise was demonstrated in the COVID-19 pandemic by identifying potential drug candidates against SARS-CoV-2 infection through the drug repurposing study, which was accomplished faster than any other research group in the world. Some drug candidates are being further developed in many countries by phase 2 and 3 clinical trials. Although we are focusing on the COVID-19 investigation right now, our research scope covers other coronaviruses (MERS-CoV and SARS-CoV), flaviviruses (Zika and dengue viruses) and bunyavirus (SFTS virus). In addition to our own research, our skills and technologies have supported drug and vaccine development of other domestic and international research institutions.

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.

Hepatitis B virus (HBV) infection is a leading cause of life-threatening liver diseases, including hepatocellular carcinoma (HCC). Chronically infected patients are treated with drugs that control the virus’s multiplication but do not cure it. The Applied Molecular Virology Laboratory developed a new HBV platform supporting the entire HBV life cycle that helped to overcome the bottleneck of recent HBV research. We developed a target-free high content screening (HCS) assay using infectious HBV particles to investigate the entire viral life cycle, which led to the identification of novel factors crucial to HBV and a new inhibitor preventing HBV from entering the liver cells and spreading from one infected cell to another. Also, a virus end-point dilution assay to determine the number of infectious HBV particles in the presence of virucidal measures was established and integrated into the drug discovery program. The 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.

Antibiotic resistance is one of the critical threats to today’s global health. To develop new antibacterial strategies against super bacteria (superbugs), the Antibacterial Resistance Lab applies the knowledge of bacterial physiology, including metabolism and mechanism of antibiotic resistance, and promotes global cooperation. Targeting Pseudomonas aeruginosa and Staphylococcus aureus, the two major causative agents of community and hospital-acquired bacterial infections, the researchers developed an innovative physiological assay system for screening compounds active against P. aeruginosa in collaboration with clinical scientists from domestic academia. Using this assay system, we successfully 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 are studying the antibacterial resistance mechanisms, especially focusing on efflux pumps in S. aureus. Additionally, as a part of the Metagenomics and Metadesign of Subways and Urban Biomes (MetaSUB), an international consortium whose goal is to understand the urban microbiome, we are investigating community-based microbiome and antibiotic resistance. Our research will provide in- depth knowledge of bacterial physiology and potentially suggest new approaches to discovering antibiotics.

Our Leishmania research program focuses on discovery of novel inhibitors of Leishmania infection with 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 one of the leading causes of death by cancer. To date, no single agent or combination therapy has demonstrated any advantage in terms of both overall survival and quality of life. A greater understanding of the cross-talk between tumor cells and their microenvironment and interactions is needed to fully understand tumor development, progression, and chemo-resistance in HCC. For this reason, the Advanced Biomedical Research Lab has established a three-dimensional tumor microenvironment that mimics the human environment and a physiologically relevant screening assay. Leveraging this innovative system, we are accelerating the identification of novel drug candidates and new targets. In addition, we are establishing a strategy to graft the three-dimensional multicellular spheroid model into the various strategies for therapeutics discovery for infectious diseases.