To combat neglected diseases, the Novartis Institute of Tropical Diseases (NITD) 
was founded in 2002 through private-public funding from Novartis and the 
Singapore Economic Development Board. One of NITD's missions is to develop 
antivirals for dengue virus (DENV), the most prevalent mosquito-borne viral 
pathogen. Neither vaccine nor antiviral is currently available for DENV. Here we 
review the progress in dengue drug discovery made at NITD as well as the major 
discoveries made by academia and other companies. Four strategies have been 
pursued to identify inhibitors of DENV through targeting both viral and host 
proteins: (i) HTS (high-throughput screening) using virus replication assays; 
(ii) HTS using viral enzyme assays; (iii) structure-based in silico docking and 
rational design; (iv) repurposing hepatitis C virus inhibitors for DENV. Along 
the developmental process from hit finding to clinical candidate, many 
inhibitors did not advance beyond the stage of hit-to-lead optimization, due to 
their poor selectivity, physiochemical or pharmacokinetic properties. Only a few 
compounds showed efficacy in the AG129 DENV mouse model. Two nucleoside analogs, 
NITD-008 and Balapiravir, entered preclinical animal safety study and clinic 
trial, but both were terminated due to toxicity and lack of potency, 
respectively. Celgosivir, a host alpha-glucosidase inhibitor, is currently under 
clinical trial; its clinical efficacy remains to be determined. The knowledge 
accumulated during the past decade has provided a better rationale for ongoing 
dengue drug discovery. Though challenging, we are optimistic that this 
continuous, concerted effort will lead to an effective dengue therapy.