Dengue Antiviral Development:  Pitfalls and opportunities

Dengue virus (DENV) infection is a public health threat to more than two-thirds of the global population and yet currently there are no approved antiviral drugs or preventive vaccines. The mission to develop treatments against dengue with directly acting antiviral (DAA) compounds or repurposed drugs has come up against “road blocks”. We recently tested celgosivir, a α-glucosidase I inhibitor, in a human clinical trial in Singapore (CELADEN). 

Despite promising pre-clinical testing data, the efficacy in humans appeared to be less prominent, suggesting that rapid kinetics of viremia reduction during acute dengue could be a major stumbling block to dengue drug development.  Indeed we found that in the AG129 mouse model, celgosivir treatment started at the peak of viremia did not significantly lower the viremia even though up to 20-fold reduction of the peak viremia could be achieved if the treatment was started at the time of infection.

Interestingly the DAA NITD008, an adenosine analog NS5 inhibitor, also failed to significantly reduce viremia reduction when treatment was started at peak viremia. Since dengue fever patients usually seek treatment at peak viremia level, it is important to develop strategies to assess drug efficacy in the correct pre-clinical setting.

This will be discussed using recent examples from our laboratory that will also touch on opportunities to develop new biomarkers to hasten dengue drug discovery.

About the speaker

Subhash Vasudevan is a Professor and Principal Investigator in the Signature Program for Emerging Infectious Diseases at Duke-National University of Singapore Graduate Medical School.  He obtained his PhD at The Australian National University (ANU) in 1989 and post-doctoral training at the Max-Planck Institute for Biophysics and Research School of Chemistry@ANU.  He established an independent research laboratory when he moved to James Cook University as a lecturer in Biochemistry and Molecular Biology (1993) and moved to Singapore to establish the Dengue Research Unit at the Novartis Institute for Tropical Diseases (2003 -2007).  His major research interest is in the area of antiviral drug discovery against dengue and related viruses.