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

  • J Med Chem. 2026 Mar 26;69(6):7111-7141. doi: 10.1021/acs.jmedchem.5c03414.
Chin Piaw Gwee  1  2 ,  Tommaso Felicetti  3 ,  Kitti Wing Ki Chan  1 ,  Min Jie Alvin Tan  1 ,  Muhammad Danial Bin Mohd Mazlan  1 ,  Ciro Milite  4 ,  Giacomo Pepe  4 ,  Chiara Sarnari  3 ,  Xiao Dan Ng  1 ,  Wint Wint Phoo  1 ,  Jasmine Hwee Yee Tan  2  5 ,  Marcus G Mah  1 ,  Satoru Watanabe  1 ,  Jing Xiu Huang  6  7 ,  Serena Massari  3 ,  Oriana Tabarrini  3 ,  Stefano Sabatini  3 ,  Pietro Campiglia  4 ,  Gianluca Sbardella  4 ,  Gavin J D Smith  1 ,  Sylvie Alonso  2  5  8 ,  Alfred Xuyang Sun  6 ,  Radoslaw M Sobota  9 ,  Subhash G Vasudevan  1  10 ,  Giuseppe Manfroni  3
Affiliations
  • 1. Program in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road, 169857 Singapore, Singapore.
  • 2. Infectious Diseases Translational Research Programme, Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, 117545 Singapore, Singapore.
  • 3. Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via Del Liceo, 1-06123 Perugia, Italy.
  • 4. Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy.
  • 5. Immunology programme, Life Sciences Institute, National University of Singapore, 117456 Singapore, Singapore.
  • 6. Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, 169857 Singapore, Singapore.
  • 7. Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, People's Republic of China.
  • 8. Communicable Diseases Agency, 307684 Singapore, Singapore.
  • 9. Institute of Molecular and Cell Biology, Agency for Science (IMCB), Technology and Research (A*STAR), 138673 Singapore, Singapore.
  • 10. Institute for Biomedicine and Glycomics, Griffith University, Southport, Queensland 4222, Australia.
PMID: 41804779 DOI: 10.1021/acs.jmedchem.5c03414
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.

Products