Antiviral drug discovery is becoming increasingly important due to the global threat of
viral disease pandemics. Many members of the genus Flavivirus are significant human pathogens, among which dengue virus (DENV) alone poses a public health threat to 2.5 billion worldwide, leading to 50-100 million human
infections each year. Neither
vaccine nor effective
therapeutics is currently available for DENV. Development of a DENV
vaccine has been challenging, because of the need to simultaneously immunize and induce a long-lasting protection against all four serotypes of DENV; an incompletely immunized individual may be sensitized to life-threatening
dengue hemorrhagic fever or
dengue shock syndrome. The challenges associated with
vaccine development have underscored the importance of development of
antiviral therapies for DENV and other flaviviruses. Here we review the strategies to identify inhibitors for DENV
therapy. Both viral and host
proteins essential for viral replication cycle are potential targets for
antiviral development. Inhibitors could be identified by multiple approaches, including
enzyme-based screening, viral replication-based screening, structure-based rational design, virtual screening, and fragment-based screening. The strategies discussed in this report should be applicable to
antiviral development of other viruses.