Inhibition of Flaviviruses by Targeting a Conserved Pocket on the Viral Envelope Protein

• Published in: Cell chemical biology Vol. 25; no. 8; pp. 1006 - 1016.e8
• Main Authors: de Wispelaere, Melissanne, Lian, Wenlong, Potisopon, Supanee, Li, Pi-Chun, Jang, Jaebong, Ficarro, Scott B., Clark, Margaret J., Zhu, Xuling, Kaplan, Jenifer B., Pitts, Jared D., Wales, Thomas E., Wang, Jinhua, Engen, John R., Marto, Jarrod A., Gray, Nathanael S., Yang, Priscilla L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 16.08.2018
• Subjects: Amino Acid Sequence; Animals; antiviral; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cell Line; Conserved Sequence; Dengue Virus - chemistry; Dengue Virus - drug effects; Dengue Virus - physiology; Drug Discovery; envelope protein inhibitor; Flavivirus - chemistry; Flavivirus - drug effects; Flavivirus - physiology; Flavivirus Infections - drug therapy; Flavivirus Infections - metabolism; Flavivirus Infections - virology; flavivirus inhibitor; Humans; inhibitor of viral entry; Molecular Docking Simulation; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Viral Envelope Proteins - chemistry; Viral Envelope Proteins - metabolism; Virus Internalization - drug effects; Virus Replication - drug effects; Zika Virus - chemistry; Zika Virus - drug effects; Zika Virus - physiology; flavivirus inhibitor; envelope protein inhibitor; inhibitor of viral entry; antiviral
• ISSN: 2451-9456; 2451-9448; 2451-9456
• DOI: 10.1016/j.chembiol.2018.05.011

Viral envelope proteins are required for productive viral entry and initiation of infection. Although the humoral immune system provides ample evidence for targeting envelope proteins as an antiviral strategy, there are few pharmacological interventions that have this mode of action. In contrast to classical antiviral targets such as viral proteases and polymerases, viral envelope proteins as a class do not have a well-conserved active site that can be rationally targeted with small molecules. We previously identified compounds that inhibit dengue virus by binding to its envelope protein, E. Here, we show that these small molecules inhibit dengue virus fusion and map the binding site of these compounds to a specific pocket on E. We further demonstrate inhibition of Zika, West Nile, and Japanese encephalitis viruses by these compounds, providing pharmacological evidence for the pocket as a target for developing broad-spectrum antivirals against multiple, mosquito-borne flavivirus pathogens. [Display omitted] •Small molecules targeting the dengue virus E protein inhibit membrane fusion•The target of these inhibitors is a pocket conserved in other flavivirus E proteins•Zika and other flaviviruses are also inhibited by compounds targeting this site•These compounds block infection without the risk of antibody-dependent enhancement Countermeasures against dengue, Zika, and other flaviviruses are a large, unmet medical need. de Wispelaere et al. validate a conserved pocket of the flavivirus envelope protein as a target for small-molecule antivirals with broad-spectrum activity against flaviviruses.