Sulfonyl Anthranilic Acid Analogues Display Pan-Serotype Anti-Dengue Activity by Downregulating the Expression of Ribosomal Proteins Encoded by 5′-Terminal Oligopyrimidine Motif-Containing mRNA

Dengue virus (DENV) remains a major global health concern without effective treatments. Previously, we identified sulfonyl anthranilic acid (SAA) derivatives (compounds <b>1</b> and <b>2</b>) as potent pan-DENV inhibitors, likely targeting a primate-specific factor. Here, mass spectrometry-based target deconvolution revealed that SAA compounds downregulate ribosomal protein expression, some of which are essential for DENV replication, as confirmed by siRNA-knockdown studies. This novel mechanism aligns with the broad-spectrum antiviral activity of compounds <b>1</b> and <b>2</b>. Moreover, compound <b>1</b> was also effective against the Zika virus in a human brain organoid model. The subsequent medicinal chemistry optimization process resulted in the identification of compound <b>7</b>, which demonstrated an EC₅₀ value of 50 nM against DENV-2, promising broad-spectrum potential and favorable <i>in vitro</i> ADME properties. Further studies indicated that these compounds modulate the 5<b>'</b>-terminal oligopyrimidine (5<b>'</b>-TOP) motif in ribosomal mRNAs. These findings open a new avenue for antiviral development by targeting a previously unexplored host pathway.