2. Academic Validation
  3. Pyridobenzothiazolones Exert Potent Anti-Dengue Activity by Hampering Multiple Functions of NS5 Polymerase

Pyridobenzothiazolones Exert Potent Anti-Dengue Activity by Hampering Multiple Functions of NS5 Polymerase

  • ACS Med Chem Lett. 2020 Mar 19;11(5):773-782. doi: 10.1021/acsmedchemlett.9b00619.
Rolando Cannalire 1,  Kitti Wing Ki Chan 2,  Maria Sole Burali 1,  Chin Piaw Gwee 2,  Sai Wang 2,  Andrea Astolfi 1,  Serena Massari 1,  Stefano Sabatini 1,  Oriana Tabarrini 1,  Eloise Mastrangelo 3 4,  Maria Letizia Barreca 1,  Violetta Cecchetti 1,  Subhash G Vasudevan 2 5 6,  Giuseppe Manfroni 1
Affiliations

Affiliations

  • 1 Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo, 1-06123 Perugia, Italy.
  • 2 Program in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road, Singapore 169857.
  • 3 Dipartimento di Bioscienze, Università di Milano, Via Celoria 26, I-20133 Milano, Italy.
  • 4 CNR-IBF, Consiglio Nazionale delle Ricerche, Istituto di Biofisica, Via Celoria 26, I-20133 Milano, Italy.
  • 5 Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4022, Australia.
  • 6 Department of Microbiology and Immunology, National University of Singapore, 5 Science Drive 2, Singapore 117545.
PMID: 32435384 DOI: 10.1021/acsmedchemlett.9b00619
Abstract

Treatment of Dengue virus (DENV) and other Flavivirus infections is an unmet medical need. The highly conserved flaviviral NS5 RNA-dependent RNA polymerase (RdRp) is an attractive Antiviral target that interacts with NS3 and viral RNA within the replication complex assembly. Biochemical and cell-based evidence indicate that targeting cavity B may lead to dual RdRp and NS5-NS3 interaction inhibitors. By ligand-based design around 1H-pyrido[2,1-b][1,3]benzothiazol-1-one (PBTZ) 1, we identified new potent and selective DENV inhibitors that exert dual inhibition of NS5 RdRp and NS3-NS5 interaction, likely through binding cavity B. Resistance studies with compound 4 generated sequence variants in the 3'-untranslated region of RNA while further biochemical experiments demonstrated its ability to block also RNA-NS5 interaction, required for correct RNA synthesis in cells. These findings shed light on the potential mechanism of action for this class of compounds, underlying how PBTZs are very promising lead candidates for further evaluation.

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