Researchers in China have conducted a study showing that a carbohydrate found in the seaweed Ecklonia kurome blocks the activity of an enzyme that is essential for the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the agent that causes coronavirus disease 2019 (COVID-19).
The seaweed – also called “Kun Bu” in China – has long been used as a medicinal plant in traditional Chinese medicine.
Kan Ding from the University of Chinese Academy of Sciences in Beijing and colleagues found that a crude polysaccharide extracted from the seaweed completely blocked the activity of an enzyme called 3C-like protease (3CLpro).
Also known as the main protease, 3CLpro is an enzyme found in coronavirusesresponsible for cleaving viral polyproteins into proteins that are essential for viral transcription and replication.
The researchers say the study suggests that this crude polysaccharide could serve as a potential drug candidate to protect against SARS-CoV-2 infection.
A pre-print version of the paper is available on the bioRxiv* server, while the article undergoes peer review.
Understanding SARS-CoV-2 infection mechanisms
Since the COVID-19 outbreak first began in Wuhan, China, in late 2019, researchers have been trying to understand the infective mechanisms of SARS-CoV-2 to help them develop effective antiviral therapies.
Researchers have established that the initial step in SARS-CoV-2 infection requires a surface viral structure called the spike protein, which binds the host cell receptor angiotensin-converting enzyme 2 (ACE2) and its co-receptor heparan sulfate.
The researchers say that the traditional Chinese medicine Ecklonia kurome contains a polysaccharide with a sulfate group at the end of its molecular chain, which may confer significant bio-activity.
The researchers propose that if heparan sulfate can bind to the spike protein, polysaccharides occurring in nature might also attach to this protein and potentially block SARS-CoV-2 infection.
“Indeed, some marine polysaccharides have been reported to inhibit SARS-Cov-2 infection in vitro, although the precise targets and mechanisms are still vague,” said Ding and colleagues.
Researchers already know that coronaviruses use the enzyme 3CLpro to cleave viral polyproteins into mature non-structural proteins such as RNA-dependent RNA polymerase (RdRp) and helicase, crucial for viral transcription and replication.
Recently, two components of the traditional Chinese herbal medicine Shuanghuanglian were shown to inhibit 3CLpro in SARS-CoV-2 and to exhibit potent antiviral activities in vitro.
“However, the detailed mechanism underlying active components against the virus is still vague,” says Ding and colleagues.
What did the researchers do?
To investigate whether Ecklonia kurome can also target 3CLpro, the team extracted a biomacromolecule polysaccharide from the seaweed, which they called 375, and examined its activity against SARS-CoV-2.
Infrared spectroscopy and nuclear magnetic resonance (NMR) imaging were used to characterize the structure of 375, as well as and three homogeneous polysaccharides (37501, 37502, and 37503) purified from the native 375 using ion-exchange chromatography.
What did they find?
The researchers found that polysaccharide 375 completely blocked the enzyme activity of 3CLpro. Furthermore, the homogeneous polysaccharide 37502 bound to 3CLpro and potently disrupted spike – ACE2 binding.
Importantly, polysaccharide 375 exhibited strong anti-SARS-CoV-2 activity in vitro, with a viral inhibition rate of 99.9% at a concentration of 20 µg/mL.
Further analysis showed that polysaccharides 37501 and 37503 also inhibited SARS-Cov-2 activity, but to a much lesser degree than the native polysaccharide 375.
Surprisingly, polysaccharide 37502 exhibited no inhibitory effects on SARS-CoV-2.
The structural analysis showed that polysaccharide 375 contains guluronic acid, mannuronic acid, mannose, rhamnose, glucuronic acid, galacturonic acid, glucose, galactose, xylose, and fucos.
Polysaccharides 37501 and 37503 were also found to contain many of these components, whereas the composition of polysaccharide 37502 was much simpler – 89.3% mannuronic acid and 10.7% guluronic acid.
What are the implications of the study?
The researchers say the results suggest that the heterogeneous polysaccharide 375 within Ecklonia kurome is much more effective at inhibiting SARS-CoV-2 activity than the individual polysaccharides 37501, 37502, and 37503.
Ding and colleagues suspect that the more potent effect observed for 375 “may be due to the cocktail-like polysaccharide exerting synergistic function through targeting multiple key molecules implicated in virus infection and replication.”
“The results also suggest that 375 may be a potential drug candidate against SARS-CoV-2,” concludes the team.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.Journal reference:
- Ding K, et al. Structural characterization of cocktail-like targeting polysaccharides from Ecklonia kurome Okam and their anti-SARS-CoV-2 activities in vitro. doi: https://doi.org/10.1101/2021.01.14.426521, https://www.biorxiv.org/content/10.1101/2021.01.14.426521v1