In a test of antiviral effectiveness against the virus that causes COVID-19, an edible seaweed extract substantially outperformed remdesivir, the current standard antiviral used to fight the disease. Credit: Rensselaer Polytechnic Institute
Heparin, a common anticoagulant, could also form the basis of a viral trap for SARS-CoV-2.
In a test of antiviral effectiveness against the virus that causes COVID-19, an edible seaweed extract substantially surpassed remdesivir, the current standard antiviral used to combat the disease. Heparin, a common anticoagulant, and a variant of heparin stripped of its anticoagulant properties, was paired with remdesivir to inhibit SARS-CoV-2 infection in mammalian cells.
Published online July 24, 2020 in Cell discoveryone, the research is the latest example of a decoy strategy that researchers from the Center for Biotechnology and Interdisciplinary Studies (CBIS) of the Rensselear Polytechnic Institute are developing against viruses such as the new coronavirus that caused the current global health crisis.
The spike protein on the surface of SARS-CoV-2 binds to the ACE-2 receptor, a molecule on the surface of human cells. Once secured, the virus inserts its own genetic material into the cell, hijacking the cellular machinery to produce replica viruses. But the virus could easily be persuaded to bind to a decoy molecule that offers a similar fit. The neutralized virus would become trapped and eventually degrade naturally.
Previous research has shown that this decoy technique works to catch other viruses, including dengue, zika, and influenza A.
“We are learning how to block viral infection, and that is the knowledge we are going to need if we are to rapidly tackle pandemics,” said Jonathan Dordick, principal investigator and professor of chemical and biological engineering at the Rensselaer Polytechnic Institute. “The reality is that we don’t have great antivirals. To protect ourselves against future pandemics, we will need an arsenal of approaches that we can quickly adapt to emerging viruses. “
the Cell discovery the paper tests antiviral activity in three heparin variants (heparin, trisulfated heparin, and one low molecular weight non-anticoagulant heparin) and two fucoidans (RPI-27 and RPI-28) extracted from seaweed. All five compounds are long chains of sugar molecules known as sulfated polysaccharides, a structural conformation that results from a binding study published earlier this month in Antiviral researchtwo suggested as an effective lure.
The researchers conducted a dose-response study known as EC50, short for the effective concentration of the compound that inhibits 50% of viral infectivity, with each of the five compounds in mammalian cells. For EC50 results, given in a molar concentration, a lower value indicates a more potent compound.
RPI-27 produced an EC50 value of approximately 83 nanomolar, while a similar previously published and independent one in vitro Testing remdesivir in the same mammalian cells produced an EC50 of 770 nanomolar. Heparin produced an EC50 of 2.1 micromolar, or approximately one third as active as remdesivir, and a non-anticoagulant analog of heparin produced an EC50 of 5.0 micromolar, approximately one fifth as active as remdesivir.
A separate test found no cellular toxicity in any of the compounds, even at the highest concentrations tested.
“What we’re interested in is a new way to contract the infection,” said Robert Linhardt, professor of chemistry and chemical biology at Rensselaer who is collaborating with Dordick to develop the decoy strategy. “The current thinking is that COVID-19 infection starts in the nose, and any one of these substances could be the basis of a nasal spray. If I could just treat the infection early, or even treat it before I had the infection, I would have a way to block it before it enters the body. “
Dordick added that the seaweed compounds “could serve as the basis for an oral administration approach to address possible gastrointestinal infection.”
By studying the SARS-CoV-2 sequencing data, Dordick and Linhardt recognized several motifs in the structure of the spike protein that promised a fit compatible with heparin, a result confirmed in the binding study. The spike protein is strongly embedded in glucans, an adaptation that protects it from human enzymes that could degrade it, and prepares it to bind to a specific receptor on the cell surface.
“It is a very complicated mechanism that we frankly don’t know all the details about, but we are getting more information,” Dordick said. “One thing that became clear from this study is that the larger the molecule, the better it fits. The most successful compounds are the largest sulfated polysaccharides that offer more sites on the molecules to trap the virus. “
Molecular modeling based on the binding study revealed sites on the spike protein where heparin could interact, increasing the chances of similar sulfated polysaccharides.
“This exciting research by Professors Dordick and Linhardt is among several ongoing research efforts at CBIS, as well as elsewhere in Rensselaer, to address the challenges of the COVID-19 pandemic through new therapeutic approaches and reuse of existing drugs, “said CBIS director Deepak Vashishth.
“Sulfate Polysaccharides Effectively Inhibit SARS-CoV-2 in vitro“It was published in Cell discovery with the support of the National Research Foundation of Korea. At Rensselaer, Dordick and Linhardt were joined in the research by Paul S. Kwon, Seok-Joon Kwon, Weihua Jin, Fuming Zhang, and Keith Fraser, and by researchers at the Korea Bioscience and Biotechnology Research Institute in Cheongju, Republic of Korea. and Zhejiang University of Technology in Hangzhou, China.
References
- “Sulfate Polysaccharides Effectively Inhibit SARS-CoV-2 In Vitro” by Paul S. Kwon, Hanseul Oh, Seok-Joon Kwon, Weihua Jin, Fuming Zhang, Keith Fraser, Jung Joo Hong, Robert J. Linhardt, and Jonathan S. Dordick, July 24, 2020, Cell discovery.
DOI: 10.1038 / s41421-020-00192-8 - “Characterization of heparin and glycoprotein binding interactions with peaks of severe acute coronavirus 2 related to acute respiratory syndrome” (SARS-CoV-2) “by So Young Kim, Weihua Jin, Amika Sood, David W. Montgomery , Oliver C. Grant, Mark M. Fuster, Li Fu, Jonathan S. Dordick, Robert J. Woods, Fuming Zhang and Robert J. Linhardt, July 10, 2020, Antiviral research.
DOI: 10.1016 / j. Antiviral. 2020.104873
