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Issue 24, 2017
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Macrocyclic peptide inhibitors for the protein–protein interaction of Zaire Ebola virus protein 24 and karyopherin alpha 5

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Abstract

Ebola virus infection leads to severe hemorrhagic fever in human and non-human primates with an average case fatality rate of 50%. To date, numerous potential therapies are in development, but FDA-approved drugs or vaccines are yet unavailable. Ebola viral protein 24 (VP24) is a multifunctional protein that plays critical roles in the pathogenesis of Ebola virus infection, e.g. innate immune suppression by blocking the interaction between KPNA and PY-STAT1. Here we report macrocyclic peptide inhibitors of the VP24–KPNA5 protein–protein interaction (PPI) by means of the RaPID (Random non-standard Peptides Integrated Discovery) system. These macrocyclic peptides showed remarkably high affinity to recombinant Zaire Ebola virus VP24 (eVP24), with a dissociation constant in the single digit nanomolar range, and could also successfully disrupt the eVP24–KPNA interaction. This work provides for the first time a chemical probe capable of modulating this PPI interaction and is the starting point for the development of unique anti-viral drugs against the Ebola virus.

Graphical abstract: Macrocyclic peptide inhibitors for the protein–protein interaction of Zaire Ebola virus protein 24 and karyopherin alpha 5

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Publication details

The article was received on 03 Jan 2017, accepted on 03 May 2017 and first published on 17 May 2017


Article type: Paper
DOI: 10.1039/C7OB00012J
Citation: Org. Biomol. Chem., 2017,15, 5155-5160
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    Macrocyclic peptide inhibitors for the protein–protein interaction of Zaire Ebola virus protein 24 and karyopherin alpha 5

    X. Song, L. Lu, T. Passioura and H. Suga, Org. Biomol. Chem., 2017, 15, 5155
    DOI: 10.1039/C7OB00012J

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