Compound FC-10696 Inhibits Egress of Marburg Virus

Marburg virus (MARV) VP40 protein (mVP40) directs egress and spread of MARV, in part, by recruiting specific host WW domain-containing proteins via its conserved PPxY late (L) domain motif to facilitate efficient virus-cell separation. We reported previously that small-molecule compounds targeting t...

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Veröffentlicht in:Antimicrobial agents and chemotherapy 2021-06, Vol.65 (7), p.e0008621-e0008621
Hauptverfasser: Han, Ziying, Ye, Hong, Liang, Jingjing, Shepley-McTaggart, Ariel, Wrobel, Jay E, Reitz, Allen B, Whigham, Alison, Kavelish, Katrina N, Saporito, Michael S, Freedman, Bruce D, Shtanko, Olena, Harty, Ronald N
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Sprache:eng
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Zusammenfassung:Marburg virus (MARV) VP40 protein (mVP40) directs egress and spread of MARV, in part, by recruiting specific host WW domain-containing proteins via its conserved PPxY late (L) domain motif to facilitate efficient virus-cell separation. We reported previously that small-molecule compounds targeting the viral PPxY/host WW domain interaction inhibited VP40-mediated egress and spread. Here, we report on the antiviral potency of novel compound FC-10696, which emerged from extensive structure-activity relationship (SAR) of a previously described series of PPxY inhibitors. We show that FC-10696 inhibits egress of mVP40 virus-like particles (VLPs) and egress of authentic MARV from HeLa cells and primary human macrophages. Moreover, FC-10696 treated-mice displayed delayed onset of weight loss and clinical signs and significantly lower viral loads compared to controls, with 14% of animals surviving 21 days following a lethal MARV challenge. Thus, FC-10696 represents a first-in-class, host-oriented inhibitor effectively targeting late stages of the MARV life cycle.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.00086-21