PMID- 33173010 OWN - NLM STAT- MEDLINE DCOM- 20210122 LR - 20210715 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 95 IP - 3 DP - 2021 Jan 13 TI - Effective Inhibition of SARS-CoV-2 Entry by Heparin and Enoxaparin Derivatives. LID - 10.1128/JVI.01987-20 [doi] LID - e01987-20 AB - 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 (IC(50)s) of 5.99 mug/liter, 1.08 mg/liter, 1.77 mug/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. CI - Copyright (c) 2021 American Society for Microbiology. FAU - Tandon, Ritesh AU - Tandon R AUID- ORCID: 0000-0001-8996-8840 AD - Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, USA. FAU - Sharp, Joshua S AU - Sharp JS AD - Department of BioMolecular Sciences, University of Mississippi, Oxford, Mississippi, USA jsharp@olemiss.edu linhar@rpi.edu. AD - Department of Chemistry and Biochemistry, University of Mississippi, Oxford, Mississippi, USA. FAU - Zhang, Fuming AU - Zhang F AD - Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, USA. FAU - Pomin, Vitor H AU - Pomin VH AD - Department of BioMolecular Sciences, University of Mississippi, Oxford, Mississippi, USA. FAU - Ashpole, Nicole M AU - Ashpole NM AD - Department of BioMolecular Sciences, University of Mississippi, Oxford, Mississippi, USA. FAU - Mitra, Dipanwita AU - Mitra D AD - Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, USA. FAU - McCandless, Martin G AU - McCandless MG AD - Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, USA. FAU - Jin, Weihua AU - Jin W AD - Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, USA. FAU - Liu, Hao AU - Liu H AD - Department of BioMolecular Sciences, University of Mississippi, Oxford, Mississippi, USA. FAU - Sharma, Poonam AU - Sharma P AD - Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, USA. FAU - Linhardt, Robert J AU - Linhardt RJ AD - Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, USA jsharp@olemiss.edu linhar@rpi.edu. LA - eng GR - 80NSSC18K1603/Intramural NASA/United States GR - P20 GM130460/GM/NIGMS NIH HHS/United States GR - P30 GM122733/GM/NIGMS NIH HHS/United States GR - R01 GM127267/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20210113 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Antiviral Agents) RN - 0 (Enoxaparin) RN - 0 (Polysaccharides) RN - 0 (Spike Glycoprotein, Coronavirus) RN - 0 (spike glycoprotein, SARS-CoV) RN - 9005-49-6 (Heparin) RN - 9050-30-0 (Heparitin Sulfate) SB - IM UOF - bioRxiv. 2020 Jun 08;:. PMID: 32577638 MH - Animals MH - Antiviral Agents/chemistry/metabolism/*pharmacology MH - Drug Evaluation, Preclinical MH - Enoxaparin/chemistry/metabolism/pharmacology MH - Genetic Vectors/genetics MH - HEK293 Cells MH - Heparin/chemistry/metabolism/*pharmacology MH - Heparitin Sulfate/metabolism MH - Humans MH - Inhibitory Concentration 50 MH - Lentivirus/genetics MH - Molecular Structure MH - Molecular Weight MH - Polysaccharides/chemistry/metabolism/pharmacology MH - Protein Binding MH - SARS-CoV-2/*drug effects/physiology MH - Spike Glycoprotein, Coronavirus/genetics/metabolism MH - Transduction, Genetic MH - Virus Attachment/drug effects MH - Virus Internalization/*drug effects PMC - PMC7925120 OTO - NOTNLM OT - COVID-19 OT - coronavirus OT - glycosaminoglycan OT - heparan sulfate OT - pseudotyping OT - spike glycoprotein EDAT- 2020/11/12 06:00 MHDA- 2021/01/23 06:00 PMCR- 2021/07/13 CRDT- 2020/11/11 05:50 PHST- 2020/10/07 00:00 [received] PHST- 2020/11/05 00:00 [accepted] PHST- 2020/11/12 06:00 [pubmed] PHST- 2021/01/23 06:00 [medline] PHST- 2020/11/11 05:50 [entrez] PHST- 2021/07/13 00:00 [pmc-release] AID - JVI.01987-20 [pii] AID - 01987-20 [pii] AID - 10.1128/JVI.01987-20 [doi] PST - epublish SO - J Virol. 2021 Jan 13;95(3):e01987-20. doi: 10.1128/JVI.01987-20. Print 2021 Jan 13.