Skip to main content

Research Repository

Advanced Search

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

Guimond, Scott; Mycroft-West, Courtney J.; Gandhi, Neha S.; Tree, Julia A.; C.Le, Thuy T.; Spalluto, 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. Thumbnail


Authors

Courtney J. Mycroft-West

Neha S. Gandhi

Julia A. Tree

Thuy T. C.Le

Mirella Spalluto

Maria V. Humbert

Karen R. Buttigieg

Naomi Coombes

Michael J. Elmore

Matthew Wand

Kristina Nyström

Joanna Said

Yin Xiang Setoh

Alberto A. Amarilla

Naphak Modhiran

Julian D. J. Sng

Mohit Chhabra

Paul R. Young

Daniel J. Rawle

Edwin A. Yates

Richard Karlsson

Rebecca L. Miller

Yen-Hsi Chen

Ieva Bagdonaite

Zhang Yang

James Stewart

Dung Nguyen

Stephen Laidlaw

Edward Hammond

Keith Dredge

Tom M. A. Wilkinson

Daniel Watterson

Alexander A. Khromykh

Andreas Suhrbier

Miles W. Carroll

Edward Trybala

Tomas Bergström

Vito Ferro



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.

Journal Article Type Article
Acceptance Date Mar 29, 2022
Publication Date May 25, 2022
Journal ACS Central Science
Print ISSN 2374-7943
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 8
Issue 5
Pages 527 - 545
DOI https://doi.org/10.1021/acscentsci.1c01293
Publisher URL https://pubs.acs.org/doi/10.1021/acscentsci.1c01293

Files




You might also like



Downloadable Citations