McIntosh, Olivia Grace (2022) Heparin: an established anticoagulant drug with therapeutic potential for COVID-19. Masters thesis, Keele University.

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Abstract

The biologically and medically important heparan sulphate and heparin polysaccharides have been previously shown to mediate viral cell entry for enveloped viruses. Furthermore, heparin and its analogues have been shown to have anti-inflammatory and anti-coagulation activity, this presents an opportunity to develop a multipronged therapeutic agent that can be used to mediate not only viral activity in vivo, but the often-accompanying inflammation and coagulopathies too. Research groups investigating the activity of heparin and its analogues have long demonstrated that heparin can inhibit a broad range of enveloped viruses, however, research regarding the novel SARS-CoV- 2 is still ongoing.

In this study, a scoping review of the current and developing research regarding heparin and SARSCoV- 2 was carried out to determine that heparin and heparin analogues not only bound SARSCoV- 2 receptor binding domain but modulated viral activity. Further investigation to determine the optimal form of heparin or type of heparin analogue revealed that low molecular weight heparins, heparin mimetics and sulphated plant compounds can exert similar, in some cases superior, viral binding inhibition when compared to standard unfractionated heparin. Of the research available, it was demonstrated that prophylactic or therapeutic heparin is associated with a reduced mortality risk, compared to other standard treatments. Despite promising results there is not an abundance of available research regarding heparin as a potential therapeutic for SARS-CoV- 2 limiting the scope of the review.

Differential scanning fluorimetry was utilised to observe the thermal destabilisation of SARS-CoV- 2 receptor binding domain in the presence and absence of heparin. This demonstrated that heparin destabilised the secondary protein structure of the SARS-CoV-2 receptor binding domain in two different mutations, UK variant and GenBank: MN908947, by 2.59°C and 2°C respectively. Investigation using an enzyme linked immunosorbent assay determined the presence of heparin inhibited the binding of SARS-CoV-2 receptor binding domain to one of its primary entry molecules, the ACE2 receptor, by 42%. Finally, a library of variably sulphated plant compounds was used to identify SARS-CoV-2 receptor binding domain inhibitors, with beneficial therapeutic attributes including low molecular weight and reduced off-target effects. Of the 29 sulphated plant compounds investigated, all had inhibitory activity on the binding activity of SARS-CoV-2 RBD to ACE2 receptors, 17 of which were more inhibitory than heparin, the most potent were HSer-C, FVes-F, HS-F and SL-K. This provides a basis of evidence that the approved drug heparin has pleiotropic effects beneficial for a disease that progresses to impact several organ systems, with multi-therapeutic effects. But may elucidate the structural requirements for the inhibitory activity displayed, which could be used to more specifically tailor a form of heparin or heparin analogue that is both effective and has minimal off-target and adverse effects.

Item Type: Thesis (Masters)
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Natural Sciences > School of Life Sciences
Contributors: Skidmore, MA (Thesis advisor)
Depositing User: Lisa Bailey
Date Deposited: 14 Oct 2022 13:57
Last Modified: 14 Oct 2022 13:57
URI: https://eprints.keele.ac.uk/id/eprint/11547

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