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Structural characterization of cocktail-like targeting polysaccharides from Ecklonia kurome Okam and their anti-SARS-CoV-2 activities invitro

Shihai Zhang, Rongjuan Pei, Meixia Li, Hao Sun, Minbo Su, Yaqi Ding, Xia Chen, Zhenyun Du, Can Jin, Chunfan Huang, Yi Zang, Jia Li, Yechun Xu, Xinwen Chen, Bo Zhang, Kan Ding
doi: https://doi.org/10.1101/2021.01.14.426521
Shihai Zhang
1Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. of China
3University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, P. R. China
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Rongjuan Pei
4State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China
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Meixia Li
1Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. of China
3University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, P. R. China
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Hao Sun
4State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China
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Minbo Su
2National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. of China
3University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, P. R. China
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Yaqi Ding
1Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. of China
3University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, P. R. China
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Xia Chen
1Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. of China
3University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, P. R. China
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Zhenyun Du
1Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. of China
3University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, P. R. China
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Can Jin
1Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. of China
3University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, P. R. China
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Chunfan Huang
1Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. of China
3University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, P. R. China
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Yi Zang
2National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. of China
3University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, P. R. China
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Jia Li
2National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. of China
3University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, P. R. China
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Yechun Xu
2National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. of China
3University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, P. R. China
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  • For correspondence: dingkan@simm.ac.cn zhangbo@wh.iov.cn chenxw@wh.iov.cn ycxu@simm.ac.cn
Xinwen Chen
4State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China
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  • For correspondence: dingkan@simm.ac.cn zhangbo@wh.iov.cn chenxw@wh.iov.cn ycxu@simm.ac.cn
Bo Zhang
4State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China
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  • For correspondence: dingkan@simm.ac.cn zhangbo@wh.iov.cn chenxw@wh.iov.cn ycxu@simm.ac.cn
Kan Ding
1Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. of China
3University of Chinese Academy of Science, No.19A Yuquan Road, Beijing 100049, P. R. China
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  • For correspondence: dingkan@simm.ac.cn zhangbo@wh.iov.cn chenxw@wh.iov.cn ycxu@simm.ac.cn
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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent responsible for the worldwide coronavirus disease 2019 (COVID-19) outbreak. Investigation has confirmed that polysaccharide heparan sulfate can bind to the spike protein and block SARS-CoV-2 infection. Theoretically, similar structure of nature polysaccharides may also have the impact on the virus. Indeed, some marine polysaccharide has been reported to inhibit SARS-Cov-2 infection in vitro, however the convinced targets and mechanism are still vague. By high throughput screening to target 3CLpro enzyme, a key enzyme that plays a pivotal role in the viral replication and transcription using nature polysaccharides library, we discover the mixture polysaccharide 375 from seaweed Ecklonia kurome Okam completely block 3Clpro enzymatic activity (IC50, 0.48 µM). Further, the homogeneous polysaccharide 37502 from the 375 may bind to 3CLpro molecule well (kD value : 4.23 × 10−6). Very interestingly, 37502 also can potently disturb spike protein binding to ACE2 receptor (EC50, 2.01 µM). Importantly, polysaccharide 375 shows good anti-SARS-CoV-2 infection activity in cell culture with EC50 values of 27 nM (99.9% inhibiting rate at the concentration of 20 µg/mL), low toxicity (LD50: 136 mg/Kg on mice). By DEAE ion-exchange chromatography, 37501, 37502 and 37503 polysaccharides are purified from native 375. Bioactivity test show that 37501 and 37503 may impede SARS-Cov-2 infection and virus replication, however their individual impact on the virus is significantly less that of 375. Surprisingly, polysaccharide 37502 has no inhibition effect on SARS-Cov-2. The structure study based on monosaccharide composition, methylation, NMR spectrum analysis suggest that 375 contains guluronic acid, mannuronic acid, mannose, rhamnose, glucouronic acid, galacturonic acid, glucose, galactose, xylose and fucose with ratio of 1.86 : 9.56 : 6.81 : 1.69 : 1.00 : 1.75 : 1.19 : 11.06 : 4.31 : 23.06. However, polysaccharide 37502 is an aginate which composed of mannuronic acid (89.3 %) and guluronic acid (10.7 %), with the molecular weight (Mw) of 27.9 kDa. These results imply that mixture polysaccharides 375 works better than the individual polysaccharide on SARS-Cov-2 may be the cocktail-like polysaccharide synergistic function through targeting multiple key molecules implicated in the virus infection and replication. The results also suggest that 375 may be a potential drug candidate against SARS-CoV-2.

Competing Interest Statement

The authors have declared no competing interest.

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Posted January 15, 2021.
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Structural characterization of cocktail-like targeting polysaccharides from Ecklonia kurome Okam and their anti-SARS-CoV-2 activities invitro
Shihai Zhang, Rongjuan Pei, Meixia Li, Hao Sun, Minbo Su, Yaqi Ding, Xia Chen, Zhenyun Du, Can Jin, Chunfan Huang, Yi Zang, Jia Li, Yechun Xu, Xinwen Chen, Bo Zhang, Kan Ding
bioRxiv 2021.01.14.426521; doi: https://doi.org/10.1101/2021.01.14.426521
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Structural characterization of cocktail-like targeting polysaccharides from Ecklonia kurome Okam and their anti-SARS-CoV-2 activities invitro
Shihai Zhang, Rongjuan Pei, Meixia Li, Hao Sun, Minbo Su, Yaqi Ding, Xia Chen, Zhenyun Du, Can Jin, Chunfan Huang, Yi Zang, Jia Li, Yechun Xu, Xinwen Chen, Bo Zhang, Kan Ding
bioRxiv 2021.01.14.426521; doi: https://doi.org/10.1101/2021.01.14.426521

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