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- Title
A Broad-Spectrum Antiviral Targeting RNA Viruses.
- Authors
Chin Piaw Gwee; Felicetti, Tommaso; Kitti Wing Ki Chan; Alonso, Sylvie; Min Jie Alvin Tan; Wint Wint Phoo; Manfroni, Giuseppe; Vasudevan, Subhash G.
- Abstract
Introduction: Dengue virus (DENV), a mosquito-borne flavivirus, continues to be a major public health threat in many countries and there are no antiviral therapeutics available. Limited protective efficacy across four dengue serotypes of the current available DENGVAXIA and QDENGA vaccine prompt the need to search for alternative. Methods: In this work, we discovered a sulfonyl anthranilic acid (SAA) derivative of the 2,1-benzothiazine 2,2-dioxide core that was previously used to develop DENV NS5 polymerase inhibitors. Dose-response inhibition experiment of SAA against DENV was performed to determine the EC50 and CC50 values. Time-of-drug-addition assay (TODA) was carried out to investigate the mechanism of action of the most potent compound - FlaR18, followed by quantification of viral RNA level and viral protein production. The efficacy of FlaR18 is also evaluated in different cell lines. Thermal proteome profiling (TPP) was performed to investigate the binding target of FlaR18. Results: Of the 38 SAA derivatives, several exhibited potent anti-DENV-2 activity in the cell-based inhibition assay, but surprisingly did not inhibit DENV NS5 polymerase activity. Notably, compound FlaR18 showed EC50 values in the range of 0.3 to 0.6 µM against the four dengue serotypes (DENV-1-4) and different RNA viruses. Time of addition assay revealed that analogue FlaR18 is a post-entry replication inhibitor that appears to be specific for cells of primate origin, implicating a host target. We have taken a high throughput proteomic approach, Cellular Thermal Shift Assay coupled to Mass Spec (MS-CETSA), to identify potential host targets that are currently being validated in gene knock out assays to elucidate the mechanism of action for compound FlaR18. Conclusion: Compound FlaR18 could serve as a lead for more potent inhibitors against the target since it also shows similar antiviral efficacy against other RNA viruses that have been tested.
- Subjects
RNA viruses; DENGUE viruses; AMINOBENZOIC acids; VIRAL proteins; FLAVIVIRUSES; POLYMERASES; SEROTYPES; GENE targeting
- Publication
Malaysian Journal of Medicine & Health Sciences, 2024, Vol 20, p57
- ISSN
1675-8544
- Publication type
Article