# 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

## TL;DR

Scientists found that sulfonyl anthranilic acid compounds can broadly inhibit dengue and Zika viruses by affecting ribosomal protein expression linked to specific mRNA motifs.

## Contribution

The study reveals a novel antiviral mechanism targeting ribosomal mRNAs with 5′-TOP motifs, offering a new host-based therapeutic strategy.

## Key findings

- Sulfonyl anthranilic acid compounds downregulate ribosomal proteins essential for DENV replication.
- Compound 1 shows efficacy against Zika virus in human brain organoids.
- Compound 7 exhibits potent antiviral activity with an EC50 of 50 nM against DENV-2.

## Abstract

Dengue virus (DENV) remains a major global health concern
without
effective treatments. Previously, we identified sulfonyl anthranilic
acid (SAA) derivatives (compounds 1 and 2) 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 1 and 2. Moreover,
compound 1 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 7, which demonstrated an EC50 value of 50 nM against
DENV-2, promising broad-spectrum potential and favorable in
vitro ADME properties. Further studies indicated that these
compounds modulate the 5′-terminal oligopyrimidine
(5′-TOP) motif in ribosomal mRNAs. These findings
open a new avenue for antiviral development by targeting a previously
unexplored host pathway.