Anticancer drug CX-5461 exerts pangenotypic anti-hepatitis E virus effect in human liver organoids and animal models

Background Hepatitis E virus (HEV) is a major cause of both acute and chronic hepatitis globally. Currently, no Food and Drug Administration-approved specific drug for HEV infection is available. There is an urgent need for the development of potent and safe anti-HEV drugs. Objective This study aimed to evaluate whether G-quadruplex (G4) ligands have anti-HEV effects and to identify candidate anti-HEV drugs. Methods We evaluated the in vitro anti-HEV activity of several G4 ligands in cancer cell lines. The lead candidate (CX-5461) was validated in multiple state-of-the-art preclinical models, including human liver organoids and a Mongolian gerbil infection model as well as an immunocompromised rabbit model for chronic HEV infection. Results Multiple G4 ligands (pyridostatin, TMPyP4 and CX-5461) significantly suppressed HEV-1 and HEV-3 infection in cellular models. CX-5461, an anticancer drug that has completed several Phase I trials, demonstrated antiviral potency in vitro at nanomolar concentrations in HEV-infected cancer cell lines and liver organoids. CX-5461 exerts its antiviral function by binding G4 structures located on the positive-strand and negative-strand RNA of the HEV genome. Using the Mongolian gerbil HEV infection model, CX-5461 was demonstrated to exhibit pangenotypic antiviral activity against clinically relevant genotypes, including HEV-1, HEV-3 and HEV-4. Importantly, CX-5461 demonstrated therapeutic efficacy against chronic HEV-3 infection at both early and stable phases of infection. Conclusion The anticancer agent CX-5461, which is already being tested for the treatment of late-stage cancers, holds promise for the treatment of HEV infections.