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

Autor:	Guimond SE; Centre for Glycoscience, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire ST5 5BG, United Kingdom., Mycroft-West CJ; Centre for Glycoscience, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire ST5 5BG, United Kingdom., Gandhi NS; School of Chemistry and Physics, Centre for Genomics and Personalized Health, Queensland University of Technology, 2 George Street, Brisbane, Queensland 4000, Australia., Tree JA; National Infection Service, UK Health Security Agency, Porton Down, Salisbury, Wiltshire SP4 0JG, United Kingdom., Le TT; QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia., Spalluto CM; School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton SO17 1BJ, United Kingdom., Humbert MV; School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton SO17 1BJ, United Kingdom., Buttigieg KR; National Infection Service, UK Health Security Agency, Porton Down, Salisbury, Wiltshire SP4 0JG, United Kingdom., Coombes N; National Infection Service, UK Health Security Agency, Porton Down, Salisbury, Wiltshire SP4 0JG, United Kingdom., Elmore MJ; National Infection Service, UK Health Security Agency, Porton Down, Salisbury, Wiltshire SP4 0JG, United Kingdom., Wand M; National Infection Service, UK Health Security Agency, Porton Down, Salisbury, Wiltshire SP4 0JG, United Kingdom., Nyström K; Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Guldhedsgatan 10B, S-413 46 Goteborg, Sweden., Said J; Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Guldhedsgatan 10B, S-413 46 Goteborg, Sweden., Setoh YX; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia.; Australian Infectious Diseases Research Centre, GVN Center of Excellence, Brisbane, Queensland 4072/4079, Australia., Amarilla AA; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia.; Australian Infectious Diseases Research Centre, GVN Center of Excellence, Brisbane, Queensland 4072/4079, Australia., Modhiran N; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia.; Australian Infectious Diseases Research Centre, GVN Center of Excellence, Brisbane, Queensland 4072/4079, Australia., Sng JDJ; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia.; Australian Infectious Diseases Research Centre, GVN Center of Excellence, Brisbane, Queensland 4072/4079, Australia., Chhabra M; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia.; Australian Infectious Diseases Research Centre, GVN Center of Excellence, Brisbane, Queensland 4072/4079, Australia., Young PR; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia.; Australian Infectious Diseases Research Centre, GVN Center of Excellence, Brisbane, Queensland 4072/4079, Australia., Rawle DJ; QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia., Lima MA; Centre for Glycoscience, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire ST5 5BG, United Kingdom., Yates EA; Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, United Kingdom., Karlsson R; Copenhagen Center for Glycomics, Department of Cellular & Molecular Medicine, University of Copenhagen, Copenhagen N 2200, Denmark., Miller RL; Copenhagen Center for Glycomics, Department of Cellular & Molecular Medicine, University of Copenhagen, Copenhagen N 2200, Denmark., Chen YH; Copenhagen Center for Glycomics, Department of Cellular & Molecular Medicine, University of Copenhagen, Copenhagen N 2200, Denmark., Bagdonaite I; Copenhagen Center for Glycomics, Department of Cellular & Molecular Medicine, University of Copenhagen, Copenhagen N 2200, Denmark., Yang Z; Copenhagen Center for Glycomics, Department of Cellular & Molecular Medicine, University of Copenhagen, Copenhagen N 2200, Denmark., Stewart J; Department of Infection Biology & Microbiomes, University of Liverpool, Liverpool L69 7ZB, United Kingdom., Nguyen D; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, Oxford University, Roosevelt Drive, Headington, Oxford OX3 7BN, United Kingdom., Laidlaw S; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, Oxford University, Roosevelt Drive, Headington, Oxford OX3 7BN, United Kingdom., Hammond E; Zucero Therapeutics Ltd, 1 Westlink Court, Brisbane, Queensland 4076, Australia., Dredge K; Zucero Therapeutics Ltd, 1 Westlink Court, Brisbane, Queensland 4076, Australia., Wilkinson TMA; School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton SO17 1BJ, United Kingdom.; NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton SO16 6YD, United Kingdom., Watterson D; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia.; Australian Infectious Diseases Research Centre, GVN Center of Excellence, Brisbane, Queensland 4072/4079, Australia., Khromykh AA; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia.; Australian Infectious Diseases Research Centre, GVN Center of Excellence, Brisbane, Queensland 4072/4079, Australia., Suhrbier A; QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia., Carroll MW; National Infection Service, UK Health Security Agency, Porton Down, Salisbury, Wiltshire SP4 0JG, United Kingdom.; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, Oxford University, Roosevelt Drive, Headington, Oxford OX3 7BN, United Kingdom., Trybala E; Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Guldhedsgatan 10B, S-413 46 Goteborg, Sweden., Bergström T; Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Guldhedsgatan 10B, S-413 46 Goteborg, Sweden., Ferro V; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia.; Australian Infectious Diseases Research Centre, GVN Center of Excellence, Brisbane, Queensland 4072/4079, Australia., Skidmore MA; Centre for Glycoscience, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire ST5 5BG, United Kingdom., Turnbull JE; Centre for Glycoscience, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire ST5 5BG, United Kingdom.; Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, United Kingdom.; Copenhagen Center for Glycomics, Department of Cellular & Molecular Medicine, University of Copenhagen, Copenhagen N 2200, Denmark.
Jazyk:	angličtina
Zdroj:	ACS central science [ACS Cent Sci] 2022 May 25; Vol. 8 (5), pp. 527-545. Date of Electronic Publication: 2022 Mar 29.
DOI:	10.1021/acscentsci.1c01293
Abstrakt:	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. Competing Interests: The authors declare the following competing financial interest(s): E. Hammond and K. Dredge are employees of Zucero Therapeutics. V. Ferro, E. Hammond, and K. Dredge are inventors on pixatimod patents. (© 2022 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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