title: Selective inhibition of Ebola entry with selective estrogen receptor modulators by disrupting the endolysosomal calcium.
abstract: The Ebola crisis occurred in West-Africa highlights the urgency for its clinical treatments. Currently, no Food and Drug Administration (FDA)-approved therapeutics are available. Several FDA-approved drugs, including selective estrogen receptor modulators (SERMs), possess selective anti-Ebola activities. However, the inhibitory mechanisms of these drugs remain elusive. By analyzing the structures of SERMs and their incidental biological activity (cholesterol accumulation), we hypothesized that this incidental biological activity induced by SERMs could be a plausible mechanism as to their inhibitory effects on Ebola infection. Herein, we demonstrated that the same dosages of SERMs which induced cholesterol accumulation also inhibited Ebola infection. SERMs reduced the cellular sphingosine and subsequently caused endolysosomal calcium accumulation, which in turn led to blocking the Ebola entry. Our study clarified the specific anti-Ebola mechanism of SERMs, even the cationic amphiphilic drugs (CADs), this mechanism led to the endolysosomal calcium as a critical target for development of anti-Ebola drugs.
authors.affiliation: State Key Laboratory of AgroBiotechnology, Faculty of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Hanlu
authors.initials: H
authors.lastname: Fan
authors.affiliation: State Key Laboratory of AgroBiotechnology, Faculty of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Du
authors.affiliation: State Key Laboratory of AgroBiotechnology, Faculty of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of AgroBiotechnology, Faculty of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Han
authors.initials: H
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of AgroBiotechnology, Faculty of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and PKU-IDG/McGovern Institute for Brain Research and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Qihui
authors.initials: Q
authors.lastname: Wu
authors.affiliation: State Key Laboratory of AgroBiotechnology, Faculty of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Han
authors.initials: H
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: George
authors.initials: G
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology and Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and PKU-IDG/McGovern Institute for Brain Research and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Zhuan
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: The University of Texas Health Science Center at San Antonio Department of Cellular and Structural Biology, San Antonio, TX 78229-3900, USA.
authors.forename: Dun-Xian
authors.initials: DX
authors.lastname: Tan
authors.affiliation: State Key Laboratory of AgroBiotechnology, Faculty of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Li
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D029043:Ebolavirus / Q000187:drug effects* / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D019142:Hemorrhagic Fever, Ebola / Q000378:metabolism* / Q000517:prevention & control; D056945:Hep G2 Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013110:Sphingosine / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D002784:Cholesterol; D013110:Sphingosine; D002118:Calcium