Selective inhibition of Ebola entry with selective estrogen receptor modulators by disrupting the endolysosomal calcium

• DOI: 10.1038/srep41226
• Publication Date: 2017-01-24T10:44:40Z
• Authors: Hanlu Fan; Xiaohong Du; Jingyuan Zhang; Han Zheng; Xiaohui Lu; Qihui Wu; Haifeng Li; Han Wang; Yi Shi; George Gao; Zhuan Zhou; Dun-Xian Tan; Xiangdong Li
• Keywords: Selective Estrogen Receptor Modulators; 0301 basic medicine; 0303 health sciences; Endosomes; Hep G2 Cells; Hemorrhagic Fever, Ebola; Ebolavirus; Article; Up-Regulation; 3. Good health; 03 medical and health sciences; Cholesterol; Receptors, Estrogen; Sphingosine; Humans; Calcium; Lysosomes

AbstractThe 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.