| Autor: |
Han Z; University of Pennsylvania, Philadelphia, Pennsylvania, USA., Ye H; Fox Chase Chemical Diversity Center, Doylestown, Pennsylvania, USA., Liang J; University of Pennsylvania, Philadelphia, Pennsylvania, USA., Shepley-McTaggart A; University of Pennsylvania, Philadelphia, Pennsylvania, USA., Wrobel JE; Fox Chase Chemical Diversity Center, Doylestown, Pennsylvania, USA., Reitz AB; Fox Chase Chemical Diversity Center, Doylestown, Pennsylvania, USA., Whigham A; Texas Biomedical Research Institute, San Antonio, Texas, USA., Kavelish KN; Texas Biomedical Research Institute, San Antonio, Texas, USA., Saporito MS; Intervir, LLC, Philadelphia, Pennsylvania, USA., Freedman BD; University of Pennsylvania, Philadelphia, Pennsylvania, USA., Shtanko O; Texas Biomedical Research Institute, San Antonio, Texas, USA., Harty RN; University of Pennsylvania, Philadelphia, Pennsylvania, USA. |
| Abstrakt: |
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. |
