Abstract
Flaviviruses cause a significant amount of mortality and morbidity, especially in regions where they are endemic. A recent example is the outbreak of Zika virus throughout the world. Development of antiviral drugs against different viral targets is as important as the development of vaccines. During viral replication, a single polyprotein precursor (PP) is produced and further cleaved into individual proteins by a viral NS2B-NS3 protease complex together with host proteases. Flavivirus protease is one of the most attractive targets for development of therapeutic antivirals because it is essential for viral PP processing, leading to active viral proteins. In this review, we have summarized recent development in drug discovery targeting the NS2B-NS3 protease of flaviviruses, especially Zika, dengue, and West Nile viruses.
Highlights
The Flavivirus genus of the Flaviviridae family includes more than 70 related arthropodborne viruses [1–4]
We have reviewed the inhibitors against the NS2B-NS3 protease of ZIKV, dengue virus (DENV), and WNV reported in literature between 2015 and 2021
This review reports the flavivirus NS2B-NS3 inhibitors developed in the last six years
Summary
The Flavivirus genus of the Flaviviridae family includes more than 70 related arthropodborne viruses [1–4]. The most common and representative members are the dengue virus (DENV) with four serotypes (DENV-1, -2, -3, and -4), Zika (ZIKV), West Nile (WNV), Yellow Fever (YFV), Japanese-encephalitis (JEV), and tick-borne encephalitis (TBEV) viruses [5–7] These are the causative agents for viral hemorrhagic fever and encephalitis in human beings. In 2019, the United States Food and Drug Administration (FDA) approved the live-attenuated, tetravalent vaccine, Dengvaxia (from Sanofi Pasteur), but only for individuals living in endemic areas between 9–16 years of age with prior DENV infection [15,16] These challenges increase the demand to develop therapeutics and vaccines that target different flaviviruses. It is plausible that a protease inhibitor for flaviviruses will be efficacious in the clinic This is evident by the fact that the NS2B-NS3 proteases from different flaviviruses, such as DENV, ZIKV, and WNV, show a high degree of similarity in their sequences and structures. Many of the active site inhibitors are only effective in biochemical assays and show low cellular antiviral activity and poor bioavailability in vivo [51]
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