Screening and Reverse-Engineering of Estrogen Receptor Ligands as Potent Pan-Filovirus Inhibitors.,Journal of Medicinal Chemistry

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Screening and Reverse-Engineering of Estrogen Receptor Ligands as Potent Pan-Filovirus Inhibitors.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-04 , DOI: 10.1021/acs.jmedchem.0c01001
Laura Cooper _{1,

2} , Adam Schafer ₂ , Yangfeng Li ₁ , Han Cheng ₂ , Bani Medegan Fagla ₂ , Zhengnan Shen ₁ , Raghad Nowar ₁ , Katherine Dye ₁ , Manu Anantpadma _{3,

4} , Robert A Davey _{3,

4} , Gregory R J Thatcher ₁ , Lijun Rong ₂ , Rui Xiong ₁

Affiliation

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.

中文翻译：

作为有效的泛丝状病毒抑制剂的雌激素受体配体的筛选和逆向工程。

丝状病毒科，包括埃博拉 (EBOV) 和马尔堡 (MARV) 病毒，是对公共健康构成严重威胁的新兴病原体。没有药物被批准用于治疗丝状病毒感染，这代表了一个主要的未满足的医疗需求。选择性雌激素受体调节剂 (SERM) 托瑞米芬先前通过与 EBOV 糖蛋白 (GP) 结合，从 FDA 批准的药物筛选中被鉴定为有效的 EBOV 病毒进入抑制剂。ER 配体的聚焦筛选将ridaifen-B 鉴定为EBOV 和MARV 的有效双重抑制剂。去除 ER 活性的优化和逆向工程导致了一种新型化合物30 ( XL-147) 显示对传染性 EBOV Zaire (0.09 μM) 和 MARV (0.64 μM) 的有效抑制。诱变研究证实，EBOV 病毒进入的抑制是由与 GP 的直接相互作用介导的。重要的是，化合物30显示出针对 Bundibugyo、Tai Forest、Reston 和 Měnglà 病毒的广谱抗丝状病毒活性，并且是第一种针对这些病毒株报道的亚微摩尔抗病毒剂，因此值得进一步开发作为泛丝状病毒抑制剂。

更新日期：2020-10-08

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