About this item:

74 Views | 55 Downloads

Author Notes:

andreas.kessel@gmx.de

LC and DKN contributed equally to this work.

The authors thank T Westfeld, E-M May, D Wiegel and W Wuebbolt (Currenta GmbH & Co. OHG, Leverkusen, Germany) for analytical services. We are deeply indebted to BE Korba (Georgetown University Medical Center, Washington, DC, USA) for conducting the HBV DNA hybridization assay, to GG Olinger and C Scully (US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA) for performing the eGFP-EBOV experiments, and to CKH Tseng (National Institutes of Health [NIH], National Institute of Allergy and Infectious Diseases [NIAID], Division of Microbiology and Infectious Diseases [DMID], Virology Branch) for supervising the wild-type EBOV experiments. We cordially thank R Koshy (NIH, NIAID, DMID, Enteric and Hepatic Diseases Branch) for helpful discussions.

The authors declare no competing interests.

Subjects:

Research Funding:

This work was supported in part by NIH CFAR grant 2P30-AI-50409 (to RFS) and by the Department of Veterans Affairs (to RFS). This project has been funded in whole or in part with Federal Funds from the DMID, NIAID, NIH, Department of Health and Human Services, under contract HHSN272201100012I. The Trinity Biomedical Sciences Institute is supported by a capital infrastructure investment from Cycle 5 of the Irish Higher Education Authority’s Programme for Research in Third Level Institutions (PRTLI). DKN would like to thank the Irish Research Council and Dell Ireland for funding. LC expressed her thanks to the Health Research Board (HRB/2007/2) for funding. We are obliged to K Hecker (HEKAtech GmbH, Wegberg, Germany) for expert elemental analyses.

Keywords:

  • Antiviral Agents
  • Ebolavirus
  • HIV-1
  • Hepacivirus
  • Hepatitis B virus
  • Humans
  • Microbial Sensitivity Tests
  • Structure-Activity Relationship
  • Thiosemicarbazones
  • Vitamin A

Retinazone inhibits certain blood-borne human viruses including Ebola virus Zaire

Tools:

Journal Title:

Antiviral Chemistry and Chemotherapy

Volume:

Volume 23, Number 5

Publisher:

, Pages 197-215

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Background: Human HBV and HIV integrate their retrotranscribed DNA proviruses into the human host genome. Existing antiretroviral drug regimens fail to directly target these intrachromosomal xenogenomes, leading to persistence of viral genetic information. Retinazone (RTZ) constitutes a novel vitamin A-derived (retinoid) thiosemicarbazone derivative with broad-spectrum antiviral activity versus HIV, HCV, varicella-zoster virus and cytomegalovirus. Methods: The in vitro inhibitory action of RTZ on HIV-1 strain LAI, human HBV strain ayw, HCV-1b strain Con1, enhanced green fluorescent protein-expressing Ebola virus Zaire 1976 strain Mayinga, wild-type Ebola virus Zaire 1976 strain Mayinga, human herpesvirus 6B and Kaposi's sarcoma-associated herpesvirus replication was investigated. The binding of RTZ to human glucocorticoid receptor was determined. Results: RTZ inhibits blood-borne human HBV multiplication in vitro by covalent inactivation of intragenic and intraexonic viral glucocorticoid response elements, and, in close analogy, RTZ suppresses HIV-1 multiplication in vitro. RTZ disrupts the multiplication of blood-borne human HCV and Ebola Zaire virus at nanomolar concentrations in vitro. RTZ has the capacity to bind to human glucocorticoid receptor, to selectively and covalently bind to intraexonic viral glucocorticoid response elements, and thereby to inactivate human genome-integrated proviral DNA of human HBV and HIV. Conclusions: RTZ represents the first reported antiviral agent capable of eradicating HIV and HBV proviruses from their human host. Furthermore, RTZ represents a potent and efficacious small-molecule in vitro inhibitor of Ebola virus Zaire 1976 strain Mayinga replication. © 2014 International Medical Press 1359-6535 (print) 2040-2066 (online).

Copyright information:

2014

Export to EndNote