| Autor: |
David Markovitz, Jasper Chan, Yoo Jin Oh, Shuofeng Yuan, Hin Chu, Man Lung Yeung, Daniel Canena, Chris Chan, Vincent Poon, Jinxia Zhang, Jian-Piao Cai, Lei Wen, Kenn Ka Heng Chik, Huiping Shuai, Yixin Wang, Yuxin Hou, Cuiting Luo, Wan-Mui Chan, Ko-Yung Sit, Wing-Kuk Au, Maureen Legendre, Rong Zhu, Lisa Hain, Kelvin To, Kwok-Hung Chan, Dafydd Thomas, Miriam Klausberger, Johannes Stadlmann, Josef Penninger, Chris Oostenbrink, Peter Hinterdorfer, Kwok-Yung Yuen |
| Rok vydání: |
2021 |
| Předmět: |
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| DOI: |
10.21203/rs.3.rs-516695/v1 |
| Popis: |
Coronaviruses have repeatedly crossed species barriers to cause epidemics1. “Pan-coronavirus” antivirals targeting conserved viral components involved in coronavirus replication, such as the extensively glycosylated spike protein, can be designed. Here we show that the rationally engineered H84T-banana lectin (H84T-BanLec), which specifically recognizes high-mannose found on viral proteins but seldom on healthy human cells2, potently inhibits the highly virulent MERS-CoV, pandemic SARS-CoV-2 and its variants, and other human-pathogenic coronaviruses at nanomolar concentrations. MERS-CoV-infected human DPP4-transgenic mice treated by H84T-BanLec have significantly higher survival, lower viral burden, and reduced pulmonary damage. Similarly, prophylactic or therapeutic H84T-BanLec is effective against SARS-CoV-2 in hamsters. Importantly, intranasally and intraperitoneally administered H84T-BanLec are comparably effective. Time-of-drug-addition assay shows that H84T-BanLec targets virus entry. Real-time structural analysis with high-speed atomic force microscopy depicts multi-molecular associations of H84T-BanLec dimers with the SARS-CoV-2 spike trimer. Single-molecule force spectroscopy demonstrates binding of H84T-BanLec to multiple SARS-CoV-2 spike mannose sites with high affinity, and that H84T-BanLec competes with SARS-CoV-2 spike for binding to cellular ACE2. Modelling experiments identify distinct high-mannose glycans in spike recognized by H84T-BanLec. The multiple H84T-BanLec binding sites on spike likely account for the activity against SARS-CoV-2 variants and the lack of resistant mutants. The broad-spectrum H84T-BanLec should be clinically evaluated in respiratory viral infections including COVID-19. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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