Identification of structurally re-engineered rocaglates as inhibitors against hepatitis E virus replication

Area of Science:

• Virology
• Medicinal Chemistry
• Hepatology

Background:

• Hepatitis E virus (HEV) is a major cause of acute viral hepatitis globally.
• Current treatments like ribavirin (RBV) and PEGylated interferon-α have limited efficacy and significant side effects.
• Rocaglates, a class of translation initiation inhibitors, have emerged as promising antiviral agents.

Purpose of the Study:

• To evaluate the antiviral properties of synthetic rocaglate derivatives against HEV.
• To identify novel therapeutic candidates for HEV infection treatment.

Main Methods:

• Screening of 205 synthetic rocaglate derivatives from the BU-CMD library against HEV genotype 3 (HEV-3).
• Antiviral activity assessed using Gaussia luciferase assay to determine EC50 values.
• Testing of selected compounds against various HEV genotypes and in primary hepatocytes.

Main Results:

• Eleven rocaglate derivatives exhibited inhibitory activity against HEV-3 replicons with EC50 values below 30 nM.
• Three amidino-rocaglates (ADRs) – CMLD012073, CMLD012118, and CMLD012612 – showed potent antiviral activity with EC50 values between 1 and 9 nM.
• These ADRs demonstrated dose-dependent inhibition against multiple HEV genotypes and were better tolerated in primary hepatocytes than cancer cell lines.

Conclusions:

• Amidino-rocaglates (ADRs), particularly CMLD012073, CMLD012118, and CMLD012612, are potential therapeutic candidates for HEV infections.
• ADRs may offer a new avenue for developing pan-genotypic HEV inhibitors.
• Combination therapy with CMLD012118 showed additive effects with existing treatments (RBV and IFN-α).