Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

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

Harvard

Guimond, SE, Mycroft-West, CJ, Gandhi, NS, Tree, JA, Le, TT, Spalluto, CM, Humbert, MV, Buttigieg, KR, Coombes, N, Elmore, MJ, Wand, M, Nyström, K, Said, J, Setoh, YX, Amarilla, AA, Modhiran, N, Sng, JDJ, Chhabra, M, Young, PR, Rawle, DJ, Lima, MA, Yates, EA, Karlsson, R, Miller, RL, Chen, YH, Bagdonaite, I, Yang, Z, Stewart, J, Nguyen, D, Laidlaw, S, Hammond, E, Dredge, K, Wilkinson, TMA, Watterson, D, Khromykh, AA, Suhrbier, A, Carroll, MW, Trybala, E, Bergström, T, Ferro, V, Skidmore, MA & Turnbull, JE 2022, 'Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction', ACS Central Science, vol. 8, no. 5, pp. 527-545. https://doi.org/10.1021/acscentsci.1c01293

APA

Guimond, S. E., Mycroft-West, C. J., Gandhi, N. S., Tree, J. A., Le, T. T., Spalluto, C. M., Humbert, M. V., Buttigieg, K. R., Coombes, N., Elmore, M. J., Wand, M., Nyström, K., Said, J., Setoh, Y. X., Amarilla, A. A., Modhiran, N., Sng, J. D. J., Chhabra, M., Young, P. R., ... Turnbull, J. E. (2022). Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction. ACS Central Science, 8(5), 527-545. https://doi.org/10.1021/acscentsci.1c01293

Vancouver

Guimond SE, Mycroft-West CJ, Gandhi NS, Tree JA, Le TT, Spalluto CM et al. Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction. ACS Central Science. 2022;8(5):527-545. https://doi.org/10.1021/acscentsci.1c01293

Author

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. / Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction. In: ACS Central Science. 2022 ; Vol. 8, No. 5. pp. 527-545.

Bibtex

@article{05c1d47e905c405da65dcc532ee3c600,

title = "Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction",

abstract = "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.",

author = "Guimond, {Scott E.} and Mycroft-West, {Courtney J.} and Gandhi, {Neha S.} and Tree, {Julia A.} and Le, {Thuy T.} and Spalluto, {C. Mirella} and Humbert, {Maria V.} and Buttigieg, {Karen R.} and Naomi Coombes and Elmore, {Michael J.} and Matthew Wand and Kristina Nystr{\"o}m and Joanna Said and Setoh, {Yin Xiang} and Amarilla, {Alberto A.} and Naphak Modhiran and Sng, {Julian D.J.} and Mohit Chhabra and Young, {Paul R.} and Rawle, {Daniel J.} and Lima, {Marcelo A.} and Yates, {Edwin A.} and Richard Karlsson and Miller, {Rebecca L.} and Chen, {Yen Hsi} and Ieva Bagdonaite and Zhang Yang and James Stewart and Dung Nguyen and Stephen Laidlaw and Edward Hammond and Keith Dredge and Wilkinson, {Tom M.A.} and Daniel Watterson and Khromykh, {Alexander A.} and Andreas Suhrbier and Carroll, {Miles W.} and Edward Trybala and Tomas Bergstr{\"o}m and Vito Ferro and Skidmore, {Mark A.} and Turnbull, {Jeremy E.}",

year = "2022",

doi = "10.1021/acscentsci.1c01293",

language = "English",

volume = "8",

pages = "527--545",

journal = "A C S Central Science",

issn = "2374-7943",

publisher = "American Chemical Society",

number = "5",

}

RIS

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.

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