Potent inhibition of highly pathogenic influenza virus infection using a peptidomimetic furin inhibitor alone or in combination with conventional antiviral agents

Antiviral medication is an important option for treatment of influenza virus infections. Two classes of anti-influenza drugs are available for prophylaxis and treatment of the infections: M2 ion channel inhibitors and neuraminidase inhibitors. However, most of the currently circulating influenza A v...

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Bibliographic Details
Main Author: Lu, Yinghui
Contributors: Garten, Wolfgang (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Language:English
Published: Philipps-Universität Marburg 2014
Hygiene u. Med. Mikrobiologie mit Medizinaluntersuchungsamt
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Summary:Antiviral medication is an important option for treatment of influenza virus infections. Two classes of anti-influenza drugs are available for prophylaxis and treatment of the infections: M2 ion channel inhibitors and neuraminidase inhibitors. However, most of the currently circulating influenza A virus strains are resistant to M2 inhibitors, and wide spread application of neuraminidase inhibitors is increasing resistance to these drugs. Therefore, discovery of new antiviral drugs and more efficient therapeutic approaches are urgently needed. The hemagglutinin (HA) protein is the major membrane glycoprotein of influenza A viruses. It facilitates binding of the virus to host cell receptors and mediates fusion between viral and endosomal membranes. Precursor HA0 must be activated by host proteases to gain its fusion capacity. The cleavage motif of HA is a major determinant of influenza virus pathogenicity. HA of highly pathogenic avian influenza virus (HPAIV) of subtypes H5 and H7 contains a multibasic cleavage motif, which is activated by the eukaryotic subtilase furin. Furin’s essential role during the HPAIV infection makes it an attractive drug target. Novel peptidomimetics imitating the furin recognition motif -R-X-K/R-R- proved to be efficacious anti-HPAIV inhibitors. They interfered with the proteolytic activation of HA and suppressed virus replication in cell cultures. Combination of oseltamivir and ribavirin with a furin inhibitor had synergistic antiviral effects. Furthermore, it suppressed the development of oseltamivir-resistant variants. Therefore, combination treatment is considered as a promising approach for the control of HPAIV.
DOI:https://doi.org/10.17192/z2014.0400