title: Glycopeptide Antibiotics Potently Inhibit Cathepsin L in the Late Endosome/Lysosome and Block the Entry of Ebola Virus, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV).
abstract: Ebola virus infection can cause severe hemorrhagic fever with a high mortality in humans. The outbreaks of Ebola viruses in 2014 represented the most serious Ebola epidemics in history and greatly threatened public health worldwide. The development of additional effective anti-Ebola therapeutic agents is therefore quite urgent. In this study, via high throughput screening of Food and Drug Administration-approved drugs, we identified that teicoplanin, a glycopeptide antibiotic, potently prevents the entry of Ebola envelope pseudotyped viruses into the cytoplasm. Furthermore, teicoplanin also has an inhibitory effect on transcription- and replication-competent virus-like particles, with an IC50 as low as 330 nm Comparative analysis further demonstrated that teicoplanin is able to block the entry of Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) envelope pseudotyped viruses as well. Teicoplanin derivatives such as dalbavancin, oritavancin, and telavancin can also inhibit the entry of Ebola, MERS, and SARS viruses. Mechanistic studies showed that teicoplanin blocks Ebola virus entry by specifically inhibiting the activity of cathepsin L, opening a novel avenue for the development of additional glycopeptides as potential inhibitors of cathepsin L-dependent viruses. Notably, given that teicoplanin has routinely been used in the clinic with low toxicity, our work provides a promising prospect for the prophylaxis and treatment of Ebola, MERS, and SARS virus infection.
authors.affiliation: From the Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, and Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhou
authors.affiliation: From the Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, and Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong.
authors.forename: Ting
authors.initials: T
authors.lastname: Pan
authors.affiliation: From the Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, and Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong.
authors.forename: Junsong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, and Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong.
authors.forename: Qianwen
authors.initials: Q
authors.lastname: Li
authors.affiliation: From the Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, and Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, and Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong.
authors.forename: Chuan
authors.initials: C
authors.lastname: Bai
authors.affiliation: From the Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, and Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong.
authors.forename: Feng
authors.initials: F
authors.lastname: Huang
authors.affiliation: the Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou 510182, Guangdong, and.
authors.forename: Tao
authors.initials: T
authors.lastname: Peng
authors.affiliation: the CAS Key Laboratory for Pathogenic Microbiology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, and Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine.
authors.forename: Liang
authors.initials: L
authors.lastname: Tao
authors.affiliation: From the Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, and Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong, zhangh92@mail.sysu.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D056668:Cathepsin L / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029043:Ebolavirus / Q000235:genetics / Q000378:metabolism*; D011992:Endosomes / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D006367:HeLa Cells; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy / Q000201:enzymology / Q000453:epidemiology; D006801:Humans; D008247:Lysosomes / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D065207:Middle East Respiratory Syndrome Coronavirus / Q000235:genetics / Q000378:metabolism*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000235:genetics / Q000378:metabolism*; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000453:epidemiology; D017334:Teicoplanin / Q000493:pharmacokinetics*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D017334:Teicoplanin; C534281:CTSL protein, human; D056668:Cathepsin L
keywords: Ebola virus; MERS-CoV; SARS-CoV; antibiotics; glycopeptide; glycoprotein; lysosome; virus entry