Your browser doesn't support javascript.
Heparin Inhibits Cellular Invasion by SARS-CoV-2: Structural Dependence of the Interaction of the Spike S1 Receptor-Binding Domain with Heparin.
Mycroft-West, Courtney J; Su, Dunhao; Pagani, Isabel; Rudd, Timothy R; Elli, Stefano; Gandhi, Neha S; Guimond, Scott E; Miller, Gavin J; Meneghetti, Maria C Z; Nader, Helena B; Li, Yong; Nunes, Quentin M; Procter, Patricia; Mancini, Nicasio; Clementi, Massimo; Bisio, Antonella; Forsyth, Nicholas R; Ferro, Vito; Turnbull, Jeremy E; Guerrini, Marco; Fernig, David G; Vicenzi, Elisa; Yates, Edwin A; Lima, Marcelo A; Skidmore, Mark A.
  • Mycroft-West CJ; Molecular and Structural Biosciences, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire, United Kingdom.
  • Su D; Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
  • Pagani I; Viral Pathogenesis and Biosafety Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Rudd TR; Analytical and Biological Sciences Division, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, United Kingdom.
  • Elli S; Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Milan, Italy.
  • Gandhi NS; School of Chemistry and Physics, Queensland University of Technology, Brisbane, Australia.
  • Guimond SE; Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
  • Miller GJ; School of Medicine, Keele University, Newcastle-Under-Lyme, Staffordshire, United Kingdom.
  • Meneghetti MCZ; School of Chemical and Physical Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire, United Kingdom.
  • Nader HB; Biochemistry Department, Federal University of São Paulo (UNIFESP), São Paulo, SP Brazil.
  • Li Y; Biochemistry Department, Federal University of São Paulo (UNIFESP), São Paulo, SP Brazil.
  • Nunes QM; Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
  • Procter P; Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
  • Mancini N; Molecular and Structural Biosciences, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire, United Kingdom.
  • Clementi M; Università Vita-Salute San Raffaele, Milan, Italy.
  • Bisio A; Università Vita-Salute San Raffaele, Milan, Italy.
  • Forsyth NR; Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Milan, Italy.
  • Ferro V; Guy Hilton Research Centre, School of Pharmacy and Bioengineering, Keele University, Hartshill, Stoke-on-Trent, Staffordshire, United Kingdom.
  • Turnbull JE; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
  • Guerrini M; Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia.
  • Fernig DG; Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
  • Vicenzi E; Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Milan, Italy.
  • Yates EA; Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
  • Lima MA; Viral Pathogenesis and Biosafety Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Skidmore MA; Molecular and Structural Biosciences, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire, United Kingdom.
Thromb Haemost ; 120(12): 1700-1715, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-998020
ABSTRACT
The dependence of development and homeostasis in animals on the interaction of hundreds of extracellular regulatory proteins with the peri- and extracellular glycosaminoglycan heparan sulfate (HS) is exploited by many microbial pathogens as a means of adherence and invasion. Heparin, a widely used anticoagulant drug, is structurally similar to HS and is a common experimental proxy. Exogenous heparin prevents infection by a range of viruses, including S-associated coronavirus isolate HSR1. Here, we show that heparin inhibits severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) invasion of Vero cells by up to 80% at doses achievable through prophylaxis and, particularly relevant, within the range deliverable by nebulisation. Surface plasmon resonance and circular dichroism spectroscopy demonstrate that heparin and enoxaparin, a low-molecular-weight heparin which is a clinical anticoagulant, bind and induce a conformational change in the spike (S1) protein receptor-binding domain (S1 RBD) of SARS-CoV-2. A library of heparin derivatives and size-defined fragments were used to probe the structural basis of this interaction. Binding to the RBD is more strongly dependent on the presence of 2-O or 6-O sulfate groups than on N-sulfation and a hexasaccharide is the minimum size required for secondary structural changes to be induced in the RBD. It is likely that inhibition of viral infection arises from an overlap between the binding sites of heparin/HS on S1 RBD and that of the angiotensin-converting enzyme 2. The results suggest a route for the rapid development of a first-line therapeutic by repurposing heparin and its derivatives as antiviral agents against SARS-CoV-2 and other members of the Coronaviridae.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Heparin / Enoxaparin / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / COVID-19 Drug Treatment / Anticoagulants Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Limits: Animals / Humans Language: English Journal: Thromb Haemost Year: 2020 Document Type: Article Affiliation country: S-0040-1721319

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Heparin / Enoxaparin / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / COVID-19 Drug Treatment / Anticoagulants Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Limits: Animals / Humans Language: English Journal: Thromb Haemost Year: 2020 Document Type: Article Affiliation country: S-0040-1721319