Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 By Disrupting The Spike-ACE2 interaction
Scott E. Guimond,
Courtney J. Mycroft-West,
Neha S Gandhi,
Julia A Tree,
Karen R Buttigieg,
Michael J. Elmore,
Yin Xiang Setoh,
Alberto A Amarilla,
Julian D.J. Sng,
Paul R Young,
Alexander A Khromykh,
Marcelo A. Lima,
Miles W Carroll,
Mark Andrew Skidmore,
Jeremy E. Turnbull
Posted 24 Jun 2020
bioRxiv DOI: 10.1101/2020.06.24.169334
Posted 24 Jun 2020
Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a co-receptor with the ACE2 protein for recognition of the S1 spike protein on SARS-CoV2 virus, revealing an attractive new target for therapeutic intervention. Clinically-used heparins demonstrate relevant inhibitory activity, but world supplies are limited, necessitating a synthetic solution. The HS mimetic pixatimod is synthetic drug candidate for cancer with immunomodulatory and heparanase-inhibiting properties. Here we show that pixatimod binds directly to the SARS-CoV-2 spike protein receptor binding domain (S1-RBD), altering its conformation and destabilizing its structure. Molecular modelling identified a binding site overlapping with the ACE2 receptor site. Consistent with this, pixatimod inhibits binding of S1-RBD to ACE2-expressing cells and displays a direct mechanism of action by inhibiting binding of S1-RBD to human ACE2. Assays with four different clinical isolates of live SARS-CoV-2 virus show that pixatimod potently inhibits infection of Vero cells at doses well within its safe therapeutic dose range. This demonstration of potent anti-SARS-CoV-2 activity establishes that synthetic HS mimetics can target the HS-Spike protein-ACE2 axis. Together with other known activities of pixatimod our data provides a strong rationale for its further investigation as a potential multimodal therapeutic to address the COVID-19 pandemic. ### Competing Interest Statement E.H. and K.D. are employees of Zucero Therapeutics. V.F., E.H. and K.D. are inventors on pixatimod patents.
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