Recent progress on phenotype-based discovery of dengue inhibitors.

Dengue fever is the world's most prevalent mosquito-borne viral disease caused by the four serotypes of dengue virus, which are widely spread throughout tropical and sub-tropical countries. There has been an urgent need to identify an effective and safe dengue inhibitor as a therapeutic and a prophylactic agent for dengue fever. Most clinically approved antiviral drugs for the treatment of human immunodeficiency syndrome-1 (HIV-1) and hepatitis C virus (HCV) target virally encoded enzymes such as protease or polymerase. Inhibitors of these enzymes were typically identified by target-based screening followed by optimization via structure-based design. However, due to the lack of success to date of research efforts to identify dengue protease and polymerase inhibitors, alternative strategies for anti-dengue drug discovery need to be considered. As a complementary approach to the target-based drug discovery, phenotypic screening is a strategy often used in identification of new chemical starting points with novel mechanisms of action in the area of infectious diseases such as antibiotics, antivirals, and anti-parasitic agents. This article is an overview of recent reports on dengue phenotypic screens and discusses phenotype-based hit-to-lead chemistry optimization. The challenges encountered and the outlook on dengue phenotype-based lead discovery are discussed at the end of this article.