Antiviral therapeutics and molecular intervention approaches for Chikungunya virus

Speaker:
Dr Justin Chu
Assistant Professor
Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore.

Host:
Dr Manoj N Krishnan
Assistant Professor, Emerging Infectious Diseases Program
Duke-NUS Graduate Medical School Singapore

Date:
Friday, 27 July, 2012

Time:
1.00pm to 2.00pm 

Venue:
Amphitheatre, Level 2
Duke-NUS Graduate Medical School
8 College Road, Singapore 169857
(opposite Singapore General Hospital, Block 6/7)

Contact Person:
Ms Serene Chee, Administrative Assistant, Emerging Infectious Diseases Program
Duke-NUS Graduate Medical School Singapore
Tel: 660 11488 or Email: serene.chee@duke-nus.edu.sg

Synopsis:
Chikungunya virus (CHIKV) is a re-emerging arthropod-borne virus responsible for recent epidemics in the Asian Pacific regions. This medically important alphavirus, Chikungunya, is known to cause CHIKV fever and disease symptoms such as maculopapular rash and persistent arthralgia in human. The current lacks of effective anti-viral or vaccine against this virus leave the human populations around the world at high risk of infection by this mosquito-borne viral pathogen.

To address this urgent need for treatment options, cell-based high-throughput screening platforms were developed in an attempt to identify potential anti-viral compounds from a diverse collection of highly purified small molecule natural product libraries against this viral pathogen. The high throughput screening of the natural product libraries using viral specific immunofluorescence assay platform have yielded an interesting primary hit list which include alkaloids, ionophores, cardiac glycosides and flavones that inhibit the different replication processes of the CHIKV (including the entry, viral RNA replication as well as assembly of virus particles). For example, a cephalotaxine alkaloid, harringtonine was selected for detailed analysis due to its strong inhibitory profile against CHIKV infection with minimal cytotoxicity. A dose-dependent study revealed harringtonine to have an IC50 of 0.45μM. Time-of-addition studies on harringtonine-treated and CHIKV-infected cells suggested that harringtonine may be involved in inhibiting the post-entry stages of viral replication during CHIKV infection. Quantitative RT-PCR studies showed drastic reduction in viral positive and negative strand RNA levels upon treatment with harringtonine. Proteomic and ultrastructural analyses further revealed that the antiviral mechanism of harringtonine as likely to be associated with the specific disruption of viral protein synthesis.

Furthermore, due to the rapid replicating nature and high genetic adaptability of the CHIKV to new strains of mosquito vector, a highly effective antiviral strategy at the viral genomic level is required. Gene silencing technologies including small hairpin RNA and morpholino oligomers targeting specific region of the CHIKV 5’ UTR, 3’ UTR, Capsid, E1, nSP1 and nSP4 genes conserved among different CHIKV phylogenic strains, were designed and evaluated. The effectiveness of these gene silencing technologies as novel antiviral approaches against CHIKV will be discussed.  These studies have provided the basis for the development of novel antiviral approaches that could be further validated for as viable therapeutic option against CHIKV infection.
 
Biography:
Dr. Justin Chu obtained his PhD in Virology from the National University of Singapore. Dr Chu continued his postdoctoral training at the Harvard Medical School where he has developed novel high throughput anti-viral drugs screening platform for dengue viruses. Recently, Dr Chu received the distinguished Lee Kuan Yew fellowship and the America Society of Microbiology Scientific Achievement Award - ICAAC Young Investigator Award. Dr Chu is currently an Assistant Professor in the Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore.  Dr. Chu’s current research laboratory is actively engaged in the application of genome-wide gene silencing technology, molecular virology, bio-imaging and proteomics techniques to study the interaction between host factors and viral components during virus replication of the mosquito-borne Dengue and Chikugunya viruses as well as human enteroviruses. By understanding the replication processes of these pathogenic viruses, Dr Chu hopes to develop novel and effective anti-viral strategies against these viruses.  Since 2001, Dr. Chu has published over 40 international peer-reviewed scientific publications, book chapters and over 90 conference papers.  A number of these scientific papers are published in prestigious journals including PNAS, Journal of Biological Chemistry, Journal of Virology and Antiviral therapy. Dr Chu is currently serving as the Singapore representative for the ASEAN Biosurveillance Initiative for Infectious Diseases and also the associate editor and reviewer for a number of peer-reviewed journals in area of medical virology and anti-viral strategies. Four patents have also been filed and generated from his current research