1 INTRODUCTION
Currently there are no licensed vaccines and limited antivirals for the
treatment of COVID-19. Repurposing existing clinical drugs with proven
safety profiles provides a rapid approach to address this gap in
treatment. Throughout the COVID-19 pandemic anticoagulant drugs such as
unfractionated heparin (UFH) and low molecular weight heparin (LMWH)
delivered systemically, have been widely used across the world as part
of standard treatment for patients in intensive care units (ICU). Use of
these drugs has been shown to be effective for dealing with
coagulopathies seen during the late stage of the disease (Kollias,
Kyriakoulis et al., 2020; Tang, Li et al., 2020). Furthermore, heparin
exhibits a wide range of anti-inflammatory properties (Mulloy, Hogwood
et al., 2016), thus providing an additional rationale of its clinical
use to treat the hyperinflammatory response observed in patients with
COVID-19.
There is a recent and growing body of evidence suggesting that UFH has
antiviral properties against SARS-CoV-2, the causative agent of
COVID-19. UFH has been shown to bind to the receptor binding domain
(RBD) of the SARS-CoV2 spike protein, which induces a conformational
change (Mycroft-West, Su et al., 2020a) and also inhibits binding of
spike protein to cells (Mycroft-West, Su et al., 2020b; Partridge, Green
et al., 2020). Additional work with a pseudotyped assay indicated that
UFH has an IC50 of 0.6 μg/ml (Tandon, Sharp et al.,
2020). Recent studies, performed with live SARS-CoV-2 and Vero E6 cells,
were limited to one heparin brand (Celsus, USA) and showed SARS-CoV-2
virus was inhibited by 44 - 80% with 6.25 μg - 200 μg/ml of UFHin vitro (Mycroft-West, Su et al., 2020b). Taking these
interesting results together, there is an urgent need for a systematic
assessment of the antiviral activity of a variety of clinically relevant
heparins, in vitro , with live wild-type SARS-CoV-2, to establish
the relative antiviral potencies of different heparins.
Independent from the systemic use of heparin in COVID-19 patients,
nebulised heparin has also been proposed as a unique and potentially
effective treatment for different stages of COVID-19 disease (van Haren,
Page et al., 2020). In the UK a clinical trial evaluating the
effectiveness of nebulised UFH in hospitalised COVID-19 patients is
currently underway (https://accord-trial.org). The strategy underpinning
this treatment stems from the positive observations made, based on
anticoagulant and anti-inflammatory activity, when running trials of
nebulised heparin in patients with acute lung injury and related
conditions (van Haren, Page et al., 2020). The delivery of an
aerosolised antiviral agent directly to the lungs where SARS-COV-2 virus
is known to be present (both upper and lower respiratory tract)
(Schaefer, Padera et al., 2020) may help to treat the alveolar
coagulopathy that is often a feature of COVID-19, reduce the
hyperinflammatory response and prevent patients from developing acute
respiratory distress syndrome (ARDS) and pulmonary fibrosis (PF), the
major complications of coronavirus infection.
Here we report for the first time a systematic assessment of the
antiviral activity of a range of heparins (UFH and LMWH) in vitroagainst live wild-type SARS-CoV-2 thereby shedding light on the
antiviral potency of a range of different heparin preparations,
including the nebulised UFH already undergoing clinical trials in
COVID-19 patients.