Compound FC-10696 Inhibits Egress and Spread of Marburg Virus

Han, Z.; Ye, H.; Liang, J.; Shepley-McTaggart, A.; Wrobel, J. E.; Reitz, A. B.; Whigham, A.; Kavelish, K. N.; Saporito, M. S.; Freedman, B.; Shtanko, O.; Harty, R. N.

doi:10.1101/2021.01.15.426918

bioRxiv · 10.1101/2021.01.15.426918

Compound FC-10696 Inhibits Egress and Spread of Marburg Virus

Han, Z.·Ye, H.·Liang, J.·Shepley-McTaggart, A.·Wrobel, J. E.·Reitz, A. B.·Whigham, A.·Kavelish, K. N.·Saporito, M. S.·Freedman, B.·Shtanko, O.·Harty, R. N.

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Abstract

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 both mVP40 VLPs and egress and spread of authentic MARV from HeLa cells and primary human macrophages. Moreover, FC-10696 treated mice displayed delayed onset of weight loss, 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 lifecycle.

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Han, Z., Ye, H., Liang, J., Shepley-McTaggart, A., Wrobel, J. E., Reitz, A. B., Whigham, A., Kavelish, K. N., Saporito, M. S., Freedman, B., Shtanko, O., Harty, R. N.. 2021-01-16. Compound FC-10696 Inhibits Egress and Spread of Marburg Virus. https://doi.org/10.1101/2021.01.15.426918

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