Screening and Reverse-Engineering of Estrogen Receptor Ligands as Potent Pan-Filovirus Inhibitors

Laura Cooper, Adam Schafer, Yangfeng Li, Han Cheng, Bani Medegan Fagla, Zhengnan Shen, Raghad Nowar, Katherine Dye, Manu Anantpadma, Robert A. Davey, Gregory R.J. Thatcher, Lijun Rong, Rui Xiong

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Filoviridae, including Ebola (EBOV) and Marburg (MARV) viruses, are emerging pathogens that pose a serious threat to public health. No agents have been approved to treat filovirus infections, representing a major unmet medical need. The selective estrogen receptor modulator (SERM) toremifene was previously identified from a screen of FDA-approved drugs as a potent EBOV viral entry inhibitor, via binding to EBOV glycoprotein (GP). A focused screen of ER ligands identified ridaifen-B as a potent dual inhibitor of EBOV and MARV. Optimization and reverse-engineering to remove ER activity led to a novel compound 30 (XL-147) showing potent inhibition against infectious EBOV Zaire (0.09 μM) and MARV (0.64 μM). Mutagenesis studies confirmed that inhibition of EBOV viral entry is mediated by the direct interaction with GP. Importantly, compound 30 displayed a broad-spectrum antifilovirus activity against Bundibugyo, Tai Forest, Reston, and Měnglà viruses and is the first submicromolar antiviral agent reported for some of these strains, therefore warranting further development as a pan-filovirus inhibitor.

Original languageEnglish (US)
Pages (from-to)11085-11099
Number of pages15
JournalJournal of Medicinal Chemistry
Volume63
Issue number19
DOIs
StatePublished - Oct 8 2020
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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