DEVELOPMENT OF NOVEL BROAD-SPECTRUM ANTIVIRALS TARGETING THE HUMAN HELICASE DDX3X

Emerging and re-emerging viruses represent a significant global health threat due to their rapid spread and potential for drug resistance. Current antiviral treatments are limited and often virus-specific, highlighting the need for broad-spectrum antivirals (BSAs). BSAs can target either conserved viral components or host cell factors essential for viral replication [1]. One promising host target is DDX3X, an RNA helicase hijacked by many viruses to aid replication and evade immune responses [2]. To date, most drug discovery efforts targeting DDX3X have focused on the development of ATPase inhibitors, which block the ATP-binding site of DDX3, and helicase inhibitors, which interfere with RNA binding and the subsequent strand unwinding process [3]. This work introduces an innovative strategy based on the development of translocation inhibitors, which bind to the binary DDX3-RNA complex, blocking a key step of viral replication. A notable example is Rocaglamide A (RocA), a natural product that inhibits both eIF4A and DDX3 and has demonstrated antiviral activity against multiple viruses [4]. In silico screening on the binary DDX3-RNA complex has led us to the selection of 14 compounds, with 9 positive hits for the inhibition of DDX3-mediated nucleic acid unwinding. Among the positive hits, the most promising compound (MR-210) showed a selective inhibition of DDX3X with a potency (IC50 = 1.67 uM) comparable to that of Rocaglamide, along with antiviral activity against different viruses. Building on these promising results, a structure-based hit-to-lead optimization has been undertaken to improve helicase inhibition and antiviral efficacy while reducing cytotoxicity. References [1] Karim M et al. , J Clin Invest. 2023 Jun 1;133(11):e170236 [2] Winnard PT Jr et al., Antiviral Res. 2021;185:104994 [3] Brai A et al. , J Med Chem. 2022 Aug 11;65(15):10195-10216 [4] Chen M et al. , Cell Chem Biol. 2021;28(4):475-486.e8