TY - JOUR

T1 - Identification of structurally re-engineered rocaglates as inhibitors against hepatitis E virus replication

AU - Praditya, Dimas F.

AU - Klöhn, Mara

AU - Brüggemann, Yannick

AU - Brown, Lauren E.

AU - Porco, John A.

AU - Zhang, Wenhan

AU - Kinast, Volker

AU - Kirschning, Andreas

AU - Vondran, Florian W.R.

AU - Todt, Daniel

AU - Steinmann, Eike

N1 - Funding Information: E.S. was supported by the German Federal Ministry of Health ( ZMVI1-2518FSB705 ) and a grant of the German Centre for Infection Diseases ( DZIF ). E.S. and A.K. were supported by the German Ministry of Education and Research ( BMBF , project SILVIR: 16GW0202 ). D.T. is funded by the German Ministry of Education and Research ( BMBF , project VirBio: 01KI2106 ].). J.A.P., Jr., W.Z., and L.E.B. were supported by the NIH grants R35GM118173 and U01TR002625 . D.F.P. received Ph.D. scholarship research funding from the DAAD (Biodiversity and Health; 57342738 ). None of the funding organizations were involved in the collection, analysis and interpretation of data, writing of the research article and in the decision to submit the article for publication.

PY - 2022/8

Y1 - 2022/8

N2 - Hepatitis E virus (HEV) infections are a leading cause of acute viral hepatitis in humans and pose a considerable threat to public health. Current standard of care treatment is limited to the off-label use of nucleoside-analog ribavirin (RBV) and PEGylated interferon-α, both of which are associated with significant side effects and provide limited efficacy. In the past few years, a promising natural product compound class of eukaryotic initiation factor 4A (eIF4A) inhibitors (translation initiation inhibitors), called rocaglates, were identified as antiviral agents against RNA virus infections. In the present study, we evaluated a total of 205 synthetic rocaglate derivatives from the BU-CMD compound library for their antiviral properties against HEV. At least eleven compounds showed inhibitory activities against the HEV genotype 3 (HEV-3) subgenomic replicon below 30 nM (EC50 value) as determined by Gaussia luciferase assay. Three amidino-rocaglates (ADRs) (CMLD012073, CMLD012118, and CMLD012612) possessed antiviral activity against HEV with EC50 values between 1 and 9 nM. In addition, these three selected compounds inhibited subgenomic replicons of different genotypes (HEV-1 [Sar55], wild boar HEV-3 [83-2] and human HEV-3 [p6]) in a dose-dependent manner and at low nanomolar concentrations. Furthermore, tested ADRs tend to be better tolerated in primary hepatocytes than hepatoma cancer cell lines and combination treatment of CMLD012118 with RBV and interferon-α (IFN-α) showed that CMLD012118 acts additive to RBV and IFN-α treatment. In conclusion, our results indicate that ADRs, especially CMLD012073, CMLD012118, and CMLD012612 may prove to be potential therapeutic candidates for the treatment of HEV infections and may contribute to the discovery of pan-genotypic inhibitors in the future.

AB - Hepatitis E virus (HEV) infections are a leading cause of acute viral hepatitis in humans and pose a considerable threat to public health. Current standard of care treatment is limited to the off-label use of nucleoside-analog ribavirin (RBV) and PEGylated interferon-α, both of which are associated with significant side effects and provide limited efficacy. In the past few years, a promising natural product compound class of eukaryotic initiation factor 4A (eIF4A) inhibitors (translation initiation inhibitors), called rocaglates, were identified as antiviral agents against RNA virus infections. In the present study, we evaluated a total of 205 synthetic rocaglate derivatives from the BU-CMD compound library for their antiviral properties against HEV. At least eleven compounds showed inhibitory activities against the HEV genotype 3 (HEV-3) subgenomic replicon below 30 nM (EC50 value) as determined by Gaussia luciferase assay. Three amidino-rocaglates (ADRs) (CMLD012073, CMLD012118, and CMLD012612) possessed antiviral activity against HEV with EC50 values between 1 and 9 nM. In addition, these three selected compounds inhibited subgenomic replicons of different genotypes (HEV-1 [Sar55], wild boar HEV-3 [83-2] and human HEV-3 [p6]) in a dose-dependent manner and at low nanomolar concentrations. Furthermore, tested ADRs tend to be better tolerated in primary hepatocytes than hepatoma cancer cell lines and combination treatment of CMLD012118 with RBV and interferon-α (IFN-α) showed that CMLD012118 acts additive to RBV and IFN-α treatment. In conclusion, our results indicate that ADRs, especially CMLD012073, CMLD012118, and CMLD012612 may prove to be potential therapeutic candidates for the treatment of HEV infections and may contribute to the discovery of pan-genotypic inhibitors in the future.

KW - Amidino-rocaglates

KW - Antiviral treatment

KW - Antivirals

KW - elF4A inhibitors

KW - Hepatitis E virus

UR - http://www.scopus.com/inward/record.url?scp=85133238680&partnerID=8YFLogxK

U2 - 10.1016/j.antiviral.2022.105359

DO - 10.1016/j.antiviral.2022.105359

M3 - Article

C2 - 35728703

AN - SCOPUS:85133238680

VL - 204

JO - Antiviral Research

JF - Antiviral Research

SN - 0166-3542

M1 - 105359

ER -