Antiviral candidates against the hepatitis E virus (HEV) and their combinations inhibit HEV growth in in vitro.

Hepatitis E is a global public health problem. Ribavirin (RBV) and pegylated interferon alpha are currently administered to cure hepatitis E. Recently, in combination with RBV, sofosbuvir (SOF), an anti-hepatitis C virus nucleotide analog, is also given to patients with chronic hepatitis E. However, this combinatorial therapy sometimes fails to achieve a sustained virological response. In this study, we used 27 antiviral compounds, including 15 nucleos(t)ide analogs, for in vitro screening against a genotype 3 HEV strain containing a Gaussia luciferase reporter. RBV, SOF, 2′- C -methyladenosine, 2′- C -methylcytidine (2CMC), 2′- C -methylguanosine (2CMG), and two 4′-azido nucleoside analogs (R-1479 and RO-9187) suppressed replication of the reporter genome, while only RBV, SOF, 2CMC and 2CMG inhibited the growth of genotype 3 HEV in cultured cells. Although 2CMG and RBV (2CMG/RBV) exhibited a synergistic effect while SOF/RBV and 2CMC/RBV showed antagonistic effects on the reporter assay, these three nucleos(t)ide analogs acted additively with RBV in inhibiting HEV growth in cultured cells. Furthermore, SOF and 2CMG, with four interferons (IFN-α2b, IFN-λ1, IFN-λ2 and IFN-λ3), inhibited HEV growth efficiently and cleared HEV in cultured cells. These results suggest that, in combination with RBV or interferons, SOF and 2CMG would be promising bases for developing anti-HEV nucleos(t)ide analogs. • We tested inhibitory effects of 27 compounds on replication of an HEV reporter genome and growth of HEV in cultured cells. • 2′- C -methylguanosine (2CMG), 2′- C -methylcytidine (2CMC) and sofosbuvir (SOF) robustly suppressed HEV growth in cultured cells. • Ribavirin (RBV) with 2CMG suppressed replication of the reporter genome synergistically but antagonistically with 2CMC or SOF. • RBV with SOF, 2CMG, or 2CMC inhibited HEV growth additively and cleared HEV in cultured cells. • SOF or 2CMG with interferon-α2b, -λ1, -λ2, or -λ3 inhibited HEV growth additively and cleared HEV in cultured cells. [ABSTRACT FROM AUTHOR]