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  • Guimond, S. E. (author)

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

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • 2022-03-29
  • American Chemical Society (ACS),2022

Numbers

  • LIBRIS-ID:oai:gup.ub.gu.se/319577
  • https://gup.ub.gu.se/publication/319577URI
  • https://doi.org/10.1021/acscentsci.1c01293DOI

Supplementary language notes

  • Language:English

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Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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.

Subject headings and genre

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  • Mycroft-West, C. J. (author)
  • Gandhi, N. S. (author)
  • Tree, J. A. (author)
  • Le, T. T. (author)
  • Spalluto, C. M. (author)
  • Humbert, M. V. (author)
  • Buttigieg, K. R. (author)
  • Coombes, N. (author)
  • Elmore, M. J. (author)
  • Wand, M. (author)
  • Nyström, Kristina,1977Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för infektionssjukdomar,Institute of Biomedicine, Department of Infectious Medicine(Swepub:gu)xnystk (author)
  • Said, JoannaGothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för infektionssjukdomar,Institute of Biomedicine, Department of Infectious Medicine(Swepub:gu)xsaijo (author)
  • Setoh, Y. X. (author)
  • Amarilla, A. A. (author)
  • Modhiran, N. (author)
  • Sng, J. D. J. (author)
  • Chhabra, M. (author)
  • Young, P. R. (author)
  • Rawle, D. J. (author)
  • Lima, M. A. (author)
  • Yates, E. A. (author)
  • Karlsson, R. (author)
  • Miller, R. L. (author)
  • Chen, Y. H. (author)
  • Bagdonaite, I. (author)
  • Yang, Z. (author)
  • Stewart, J. (author)
  • Nguyen, D. (author)
  • Laidlaw, S. (author)
  • Hammond, E. (author)
  • Dredge, K. (author)
  • Wilkinson, T. M. A. (author)
  • Watterson, D. (author)
  • Khromykh, A. A. (author)
  • Suhrbier, A. (author)
  • Carroll, M. W. (author)
  • Trybala, Edward,1955Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för infektionssjukdomar,Institute of Biomedicine, Department of Infectious Medicine(Swepub:gu)xtryed (author)
  • Bergström, Tomas,1950Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för infektionssjukdomar,Institute of Biomedicine, Department of Infectious Medicine(Swepub:gu)xberto (author)
  • Ferro, V. (author)
  • Skidmore, M. A. (author)
  • Turnbull, J. E. (author)
  • Göteborgs universitetInstitutionen för biomedicin, avdelningen för infektionssjukdomar (creator_code:org_t)

Related titles

  • In:ACS Central Science: American Chemical Society (ACS)8:5, s. 527-5452374-79432374-7951

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