Application of Chemical Genetics in Identifying Novel Druggable Targets

Speaker:

Dr Richard Yi Tsun KAO

B.Sc.(Hons), Ph.D. University of British Columbia

Department of Microbiology

University of Hong Kong

Host:
Assistant Professor Manoj Krishnan
Program in Emerging Infectious Diseases
Duke-NUS Graduate Medical School

Date:
Tuesday , 5 June 2012

Time:
3.00 PM — 4.00 PM

Contact Person:
Ms Serene Chee

Administrative Assistant

Emerging Infectious Diseases Program

Tel: 660 11488          Email: serene.chee@duke-nus.edu.sg

Venue:
Conference 4D, Level 4
Duke-NUS Graduate Medical School
8 College Road, Singapore 169857
(opposite Singapore General Hospital, Block 6/7)

Synopsis: 

Viral infection continues to be a big threat to mankind and drug resistance to available antivirals is appearing in an alarming rate. There is an urgent need to identify new druggable targets and find new antiviral drugs in light of rapid emerging and re-emerging viral pathogens. Our first success in applying forward chemical genetics to identify biologically active small molecule inhibitors of SARS-CoV in 2004 (Kao et al., Chemistry & Biology, 11:1293) has prompted us to tackle influenza A virus pathogenesis using this novel approach. Applying the concept of chemical genetics, after screening 50,240 structurally diverse compounds using an automated high-throughput screening (HTS) platform, we have identified more than 1,000 small-molecule compounds that inhibited the infectivity of the viruses in mammalian cell-based assays. Subsequent secondary screening with 950 selected hits has identified 39 potent anti-influenza A compounds. The binding site of compound nucleozin was mapped to residue Y289 of NP by molecular modeling and mutational studies. Balb-c mice treated by nucleozin were protected from the lethal infection of a hyper-virulent strain of influenza A H5N1/Vietnam/1194/04, illustrating the in vivo efficacy of nucleozin in inhibiting H5N1 infection. Further investigation revealed that nucleozin induces specific aggregation of NP and this novel drug-induced aggregation phenomenon halts the cellular trafficking of NP and abolishes the biological activities of this crucial component of the virus.  Our results demonstrate that chemical genetics is a powerful tool for the identification of druggable targets, new antiviral drugs, and novel antiviral mechanisms.

Biography:

Dr. Richard Yi Tsun KAO obtained his Ph. D. (Microbiology) in 1999 under the supervision of Julian Davies at the University of British Columbia, Vancouver, Canada, and received subsequent postdoctoral training at Harvard Medical School, Boston. He joined the University of Hong Kong in 2001 and started his career as a Research Assistant Professor, first in HKU-Pasture Research Center, and subsequently in the Department of Microbiology, Li Ka Shing Faculty of Medicine, the University of Hong Kong. Now he is the Assistant Professor, Department of Microbiology, and also the Director of Chemical Genetics Unit, Research Center of Infection and Immunology at HKU. Currently Dr. Kao’s research focuses on the application of chemical genetics in infectious diseases. His work on SARS-associated coronavirus (SARS-CoV), which was published in Chemistry & Biology in 2004, has established the world’s first model of chemical genetics in virology and illustrated that chemical genetics approach could be employed to probe most, if not all, pathogenic pathways of a virus. After the SARS work, Dr. Kao’s team employed similar approach to identify new druggable targets in influenza virus. Recently, he has published an article in Nature Biotechnology detailing their groundbreaking discovery of viral nucleoprotein as a druggable target and a compound nucleozin that antagonizes the influenza A nucleoprotein. Trained as a microbiologist, Dr. Kao’s interests span from virology to mycology and his pioneering work in applying chemical genetics in microbiology has sparked new directions of research in infectious diseases.