Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction
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Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction. / Guimond, Scott E.; Mycroft-West, Courtney J.; Gandhi, Neha S.; Tree, Julia A.; Le, Thuy T.; Spalluto, C. Mirella; Humbert, Maria V.; Buttigieg, Karen R.; Coombes, Naomi; Elmore, Michael J.; Wand, Matthew; Nyström, Kristina; Said, Joanna; Setoh, Yin Xiang; Amarilla, Alberto A.; Modhiran, Naphak; Sng, Julian D.J.; Chhabra, Mohit; Young, Paul R.; Rawle, Daniel J.; Lima, Marcelo A.; Yates, Edwin A.; Karlsson, Richard; Miller, Rebecca L.; Chen, Yen Hsi; Bagdonaite, Ieva; Yang, Zhang; Stewart, James; Nguyen, Dung; Laidlaw, Stephen; Hammond, Edward; Dredge, Keith; Wilkinson, Tom M.A.; Watterson, Daniel; Khromykh, Alexander A.; Suhrbier, Andreas; Carroll, Miles W.; Trybala, Edward; Bergström, Tomas; Ferro, Vito; Skidmore, Mark A.; Turnbull, Jeremy E.
In: ACS Central Science, Vol. 8, No. 5, 2022, p. 527-545.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction
AU - Guimond, Scott E.
AU - Mycroft-West, Courtney J.
AU - Gandhi, Neha S.
AU - Tree, Julia A.
AU - Le, Thuy T.
AU - Spalluto, C. Mirella
AU - Humbert, Maria V.
AU - Buttigieg, Karen R.
AU - Coombes, Naomi
AU - Elmore, Michael J.
AU - Wand, Matthew
AU - Nyström, Kristina
AU - Said, Joanna
AU - Setoh, Yin Xiang
AU - Amarilla, Alberto A.
AU - Modhiran, Naphak
AU - Sng, Julian D.J.
AU - Chhabra, Mohit
AU - Young, Paul R.
AU - Rawle, Daniel J.
AU - Lima, Marcelo A.
AU - Yates, Edwin A.
AU - Karlsson, Richard
AU - Miller, Rebecca L.
AU - Chen, Yen Hsi
AU - Bagdonaite, Ieva
AU - Yang, Zhang
AU - Stewart, James
AU - Nguyen, Dung
AU - Laidlaw, Stephen
AU - Hammond, Edward
AU - Dredge, Keith
AU - Wilkinson, Tom M.A.
AU - Watterson, Daniel
AU - Khromykh, Alexander A.
AU - Suhrbier, Andreas
AU - Carroll, Miles W.
AU - Trybala, Edward
AU - Bergström, Tomas
AU - Ferro, Vito
AU - Skidmore, Mark A.
AU - Turnbull, Jeremy E.
N1 - Publisher Copyright: © 2022 American Chemical Society. All rights reserved.
PY - 2022
Y1 - 2022
N2 - Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a coreceptor with the ACE2 protein for the S1 spike protein on SARS-CoV-2 virus, providing a tractable new therapeutic target. Clinically used heparins demonstrate an inhibitory activity but have an anticoagulant activity and are supply-limited, necessitating alternative solutions. Here, we show that synthetic HS mimetic pixatimod (PG545), a cancer drug candidate, binds and destabilizes the SARS-CoV-2 spike protein receptor binding domain and directly inhibits its binding to ACE2, consistent with molecular modeling identification of multiple molecular contacts and overlapping pixatimod and ACE2 binding sites. Assays with multiple clinical isolates of SARS-CoV-2 virus show that pixatimod potently inhibits the infection of monkey Vero E6 cells and physiologically relevant human bronchial epithelial cells at safe therapeutic concentrations. Pixatimod also retained broad potency against variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Furthermore, in a K18-hACE2 mouse model, pixatimod significantly reduced SARS-CoV-2 viral titers in the upper respiratory tract and virus-induced weight loss. This demonstration of potent anti-SARS-CoV-2 activity tolerant to emerging mutations establishes proof-of-concept for targeting the HS-Spike protein-ACE2 axis with synthetic HS mimetics and provides a strong rationale for clinical investigation of pixatimod as a potential multimodal therapeutic for COVID-19.
AB - Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a coreceptor with the ACE2 protein for the S1 spike protein on SARS-CoV-2 virus, providing a tractable new therapeutic target. Clinically used heparins demonstrate an inhibitory activity but have an anticoagulant activity and are supply-limited, necessitating alternative solutions. Here, we show that synthetic HS mimetic pixatimod (PG545), a cancer drug candidate, binds and destabilizes the SARS-CoV-2 spike protein receptor binding domain and directly inhibits its binding to ACE2, consistent with molecular modeling identification of multiple molecular contacts and overlapping pixatimod and ACE2 binding sites. Assays with multiple clinical isolates of SARS-CoV-2 virus show that pixatimod potently inhibits the infection of monkey Vero E6 cells and physiologically relevant human bronchial epithelial cells at safe therapeutic concentrations. Pixatimod also retained broad potency against variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Furthermore, in a K18-hACE2 mouse model, pixatimod significantly reduced SARS-CoV-2 viral titers in the upper respiratory tract and virus-induced weight loss. This demonstration of potent anti-SARS-CoV-2 activity tolerant to emerging mutations establishes proof-of-concept for targeting the HS-Spike protein-ACE2 axis with synthetic HS mimetics and provides a strong rationale for clinical investigation of pixatimod as a potential multimodal therapeutic for COVID-19.
U2 - 10.1021/acscentsci.1c01293
DO - 10.1021/acscentsci.1c01293
M3 - Journal article
C2 - 35647275
AN - SCOPUS:85127971568
VL - 8
SP - 527
EP - 545
JO - A C S Central Science
JF - A C S Central Science
SN - 2374-7943
IS - 5
ER -
ID: 342927703