Effective Inhibition of SARS-CoV-2 Entry by Heparin and Enoxaparin Derivatives.
Ritesh Tandon,Joshua S. Sharp,Fuming Zhang,Vitor H. Pomin,Nicole M. Ashpole,Dipanwita Mitra,Martin G. McCandless,Weihua Jin,Hao Liu,Poonam Sharma,Robert J. Linhardt +10 more
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TLDR
Several sulfated polysaccharides show potent anti-SARS-CoV-2 activity and can be developed for prophylactic as well as therapeutic purposes, according to structure-based differences in antiviral activity and affinity to SGP.Abstract:
Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has caused a pandemic of historic proportions and continues to spread globally, with enormous consequences to human health. Currently there is no vaccine, effective therapeutic, or prophylactic. As with other betacoronaviruses, attachment and entry of SARS-CoV-2 are mediated by the spike glycoprotein (SGP). In addition to its well-documented interaction with its receptor, human angiotensin-converting enzyme 2 (hACE2), SGP has been found to bind to glycosaminoglycans like heparan sulfate, which is found on the surface of virtually all mammalian cells. Here, we pseudotyped SARS-CoV-2 SGP on a third-generation lentiviral (pLV) vector and tested the impact of various sulfated polysaccharides on transduction efficiency in mammalian cells. The pLV vector pseudotyped SGP efficiently and produced high titers on HEK293T cells. Various sulfated polysaccharides potently neutralized pLV-S pseudotyped virus with clear structure-based differences in antiviral activity and affinity to SGP. Concentration-response curves showed that pLV-S particles were efficiently neutralized by a range of concentrations of unfractionated heparin (UFH), enoxaparin, 6-O-desulfated UFH, and 6-O-desulfated enoxaparin with 50% inhibitory concentrations (IC50s) of 5.99 µg/liter, 1.08 mg/liter, 1.77 µg/liter, and 5.86 mg/liter, respectively. In summary, several sulfated polysaccharides show potent anti-SARS-CoV-2 activity and can be developed for prophylactic as well as therapeutic purposes.IMPORTANCE The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV-2) in Wuhan, China, in late 2019 and its subsequent spread to the rest of the world has created a pandemic situation unprecedented in modern history. While ACE2 has been identified as the viral receptor, cellular polysaccharides have also been implicated in virus entry. The SARS-CoV-2 spike glycoprotein (SGP) binds to glycosaminoglycans like heparan sulfate, which is found on the surface of virtually all mammalian cells. Here, we report structure-based differences in antiviral activity and affinity to SGP for several sulfated polysaccharides, including both well-characterized FDA-approved drugs and novel marine sulfated polysaccharides, which can be developed for prophylactic as well as therapeutic purposes.read more
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SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2.
Thomas Mandel Clausen,Thomas Mandel Clausen,Thomas Mandel Clausen,Daniel R. Sandoval,Charlotte B Spliid,Charlotte B Spliid,Charlotte B Spliid,Jessica Pihl,Jessica Pihl,Jessica Pihl,Hailee R. Perrett,Chelsea D. Painter,Anoop Narayanan,Sydney A. Majowicz,Elizabeth M. Kwong,Rachael N. McVicar,Bryan E. Thacker,Charles A. Glass,Zhang Yang,Jonathan L. Torres,Gregory J. Golden,Phillip L. Bartels,Ryan N. Porell,Aaron F. Garretson,Logan K. Laubach,Jared Feldman,Xin Yin,Yuan Pu,Blake M. Hauser,Timothy M. Caradonna,Benjamin P. Kellman,Cameron Martino,Philip L.S.M. Gordts,Sumit K. Chanda,Aaron G. Schmidt,Aaron G. Schmidt,Kamil Godula,Sandra L Leibel,Joyce Jose,Kevin D. Corbett,Andrew B. Ward,Aaron F. Carlin,Jeffrey D. Esko +42 more
TL;DR: A model in which viral attachment and infection involves heparan sulfate-dependent enhancement of binding to ACE2 is suggested, in which Manipulation of hepara sulfate or inhibition of viral adhesion by exogenous heparin presents new therapeutic opportunities.
Journal ArticleDOI
Characterization of heparin and severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions.
So Young Kim,So Young Kim,Weihua Jin,Amika Sood,David W. Montgomery,Oliver C. Grant,Mark M. Fuster,Li Fu,Jonathan S. Dordick,Robert J. Woods,Fuming Zhang,Robert J. Linhardt +11 more
TL;DR: Use of a surface plasmon resonance direct binding assay and unbiased computational ligand docking indicates that heparan sulfate interacts with the GAG-binding motif at the S1/S2 site on each monomer interface in the trimeric SARS-CoV-2 SGP, and at another site when the receptor-binding domain is in an open conformation.
Journal ArticleDOI
Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study.
Christopher T Rentsch,Christopher T Rentsch,Joshua A. Beckman,Laurie A. Tomlinson,Walid F. Gellad,Walid F. Gellad,Charles Alcorn,Farah Kidwai-Khan,Farah Kidwai-Khan,Melissa Skanderson,Evan L. Brittain,Joseph T. King,Joseph T. King,Yuk-Lam Ho,Svetlana K. Eden,Suman Kundu,Michael F. Lann,Robert A. Greevy,P. Michael Ho,Paul A. Heidenreich,Paul A. Heidenreich,Daniel Jacobson,Ian J. Douglas,Janet P. Tate,Janet P. Tate,Stephen J. W. Evans,David C. Atkins,Amy C. Justice,Amy C. Justice,Matthew S Freiberg,Matthew S Freiberg +30 more
TL;DR: Early initiation of prophylactic anticoagulation was associated with decreased risk of death among patients admitted to hospital with coronavirus disease 2019 (covid-19) in the United States.
Journal ArticleDOI
Beneficial non-anticoagulant mechanisms underlying heparin treatment of COVID-19 patients.
TL;DR: In this paper, potential beneficial, non-anticoagulant mechanisms underlying treatment of colonavirus disease-2019 patients with heparin/low molecular weight (LMWH) were summarized.
Journal ArticleDOI
Cell entry by SARS-CoV-2.
TL;DR: In this paper, the authors discuss the recent advances in understanding the molecular events during SARS-CoV-2 entry which will contribute to developing vaccines and therapeutics, and discuss some auxiliary receptors and cofactors are also involved that expand the host/tissue tropism.
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TL;DR: Detailed virological analysis of nine cases of coronavirus disease 2019 (COVID-19) provides proof of active replication of the SARS-CoV-2 virus in tissues of the upper respiratory tract.
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