Corona versus Dengue: Distinct Mechanisms for Inhibition of Polyprotein Processing by Antiviral Drugs.

Inhibitors interfering with processing of the viral polyprotein are used successfully for the control of extremely important viral pathogens, such as HIV and most recently SARS-CoV-2. This Viewpoint provides a mechanistic evaluation of a promising antiviral lead compound against dengue virus, JNJ-A07, 4-(3-((1-(4-chlorophenyl)-2-oxo-2-(6-(trifluoromethoxy)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid. The antiviral effect of JNJ-A07 appears, in our opinion, to be connected to an interference with the function of the viral protease. The analysis reveals for the first time that antiviral drugs target polyprotein processing not only by direct inhibition, but also by disturbing the native sequence of cleavage events. Implications on the development of broad-spectrum antivirals against flaviviruses are addressed.