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 IC 50 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 additionalglycopeptidesaspotentialinhibitorsofcathepsinL-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.

Novel activities of safe-in-human broad-spectrum antiviral agents

“…Dalbavancin also inhibits MERS-CoV and SARS-CoV infections. It binds cathepsin L in the late endosomes/lysosomes and blocks the entry of EBOV (Zhou et al, 2016). Our study demonstrates that it also inhibits replication of EV1, which also enters the cells via an endocytic route (Krieger et al, 2013).…”

“…Oritavancin is a semisynthetic glycopeptide antibiotic used for the treatment of Gram-positive bacterial skin infections. It also inhibits EBOV, MERS-CoV, and SARS-CoV infections (Zhou et al, 2016). Ritonavir is an antiretroviral medication.…”

Structure-activity relationship studies of lipophilic teicoplanin pseudoaglycon derivatives as new anti-influenza virus agents

“…Activity against human coronavirus 229E. Given that teicoplanin and related glycopeptides were reported to have anticoronavirus activity [10,11], we evaluated a subset of the newly synthesized compounds against human coronavirus 229E, using two complementary methods, i.e. CPE reduction in human embryonic lung (HEL) fibroblast cells and virus yield reduction in human lung carcinoma A549 cells.…”

“…relevant since they often display broad activity against influenza plus some other emerging viruses. Derivatives of teicoplanin or related antibiotics were reported to inhibit, among others, influenza virus [9]; coronaviruses [10] including SARS-CoV (severe acute respiratory syndrome coronavirus) [11]; Ebola pseudovirus [12]; HIV [13]; or hepatitis C virus [14]. Our focus of the last years was to investigate the structure-activity relationship and mechanism of action for influenza virus.…”

Lectin Affinity Plasmapheresis for Middle East Respiratory Syndrome-Coronavirus and Marburg Virus Glycoprotein Elimination

“…Currently, many efforts for effective vaccines are made (MERS-CoV see e.g., [28], MARV, EBOV see e.g., [29]) and inter alia promising virus-like particles evaluated for immunization [30]. Also, existing medications like interferon-α2b, teicoplanin, or eritoran are considered for usage, convalescent plasma is given, and promising antiviral therapies are developed [19, 31-33]. Still, none of them has qualified for wide scale use up to now.…”