A recent paper available on the preprint server bioRxiv* reports preliminary data on the ability of low molecular weight heparins to interact with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), elicit structural changes in its key proteins and subsequently halt cell invasion.
With most of the world currently in lockdown, SARS-CoV-2 that causes coronavirus disease 2019 (COVID-19), is one of the biggest public threats we have ever faced due to its ease of spread and reported case-fatality rates.
At the moment, there are no commercially available drugs or medical products designed to treat or prevent COVID-19. A vaccine is also not available, although some have entered the preliminary testing phase in people.
But even moderately effective treatment approaches may dramatically lessen the burden on hospitals and intensive care units, modifying, in turn, the risk of this new pathogen to various populations and health care systems worldwide.
Novel Coronavirus SARS-CoV-2: This scanning electron microscope image shows SARS-CoV-2 (round gold objects) emerging from the surface of cells cultured in the lab. SARS-CoV-2, also known as 2019-nCoV, is the virus that causes COVID-19. The virus shown was isolated from a patient in the U.S. Credit: NIAID-RML
Drug repurposing research as a way forward
Traditional drug development procedures are rather slow and ineffective against emerging public health issues such as the current COVID-19 pandemic, which makes the repurposing of existing drugs an opportune and attractive alternative.
"Studying SARS-CoV-2 Spike protein structure and behavior in solution is a vital step for the development of effective therapeutics against SARS-CoV-2", say the research group from the UK and Italy. They turned their eye towards low molecular weight heparins in their new research paper available on bioRxiv.
Heparin, which is a well-tolerated anticoagulant drug, has been safely used in medicine for over eighty years. Alongside its notable anticoagulant activities, its propensity to prevent viral infection – including those caused by coronaviruses – has been described.
Heparin-induced conformational changes
The same research group has previously shown how unfractionated heparins bind to the Spike (S1) protein receptor-binding domain of SARS-CoV-2 and induces a conformational change. They have also reported the structural features of heparin on which this interaction depends.
Furthermore, they have demonstrated that enoxaparin (which is a low molecular weight clinical anticoagulant) binds the S1 receptor binding domain protein and induces conformational change.
Now they expand upon these studies by including a wide array of low molecular weight heparins, demonstrating how they induce a plethora of conformational changes in the SARS-CoV-2 receptor binding domain.
In this study, they have used spectroscopic methods to study the ability of the SARS-CoV-2 S1 receptor binding domain to bind pharmaceutical low molecular weight heparins. More specifically, circular dichroism spectroscopy was used to confirm changes in protein secondary structure that occur in solution by using ultraviolet radiation.
The ensuing conformational changes impede the viral attachment to glycosaminoglycans (GAG), which are carbohydrates present on basically all mammalian cells that play a pivotal role in coronavirus cell invasion.
From prophylaxis to intensive care treatment
"The GAG heparin has previously been shown to inhibit SARS-associated coronavirus cell invasion, and this, in concert with the low molecular weight heparin data presented within this study, supports the use of GAG-derived pharmaceuticals as therapeutic agents against SARS-associated coronavirus", study authors highlight the significance of their findings.
In addition, this study provides ample evidence for the repurposing of low molecular weight heparins as antiviral agents, providing a potentially rapid counter-attack against the current pandemic.
"Such drugs will be amenable to routine parenteral administration through currently established routes and additionally, direct to the respiratory tract via nasal administration, using nebulized heparins, which would be unlikely to gain significant access to the circulation," say study authors.
"Thus, the anticoagulant activity of unfractionated heparins and low molecular weight heparins, which can, in any event, be engineered out, would not pose a problem," they add.
Furthermore, such an administration route would not only be amenable for prophylaxis, but also for patients that necessitate mechanical ventilation – clearly showing the vast potential of this approach.
The promise of heparin
It has to be emphasized that even pharmaceutical-grade unfractionated heparin and low molecular weight heparin preparations remain a polydisperse assortment of natural products, encompassing both anticoagulant and non-anticoagulant saccharide structures.
These may prove to be an indispensable resource for the new era of biologically active, antiviral agents that show negligible anticoagulant potential due to various chemical engineering procedures to wear down their anticoagulation properties.
The further sub-fractionation of available low molecular weight heparin preparations against anticoagulant activities (with already proven low-toxicity, good bioavailability, and industrial scaling) for off-label pathologies is an attractive strategy for an effective response to COVID-19 threat.
bioRxiv publishes preliminary reports that are not peer-reviewed and, therefore, not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Mycroft-West, C.J. et al. (2020). SARS-CoV-2 Spike S1 Receptor Binding Domain undergoes Conformational Change upon Interaction with Low Molecular Weight Heparins. bioRxiv. https://doi.org/10.1101/2020.04.29.068486