tetano
Editor, Senior Moderator
J Virol
. 2020 Nov 10;JVI.01987-20.
doi: 10.1128/JVI.01987-20. Online ahead of print.
Effective Inhibition of SARS-CoV-2 Entry by Heparin and Enoxaparin Derivatives
Ritesh Tandon[SUP] 1 [/SUP], Joshua S Sharp[SUP] 2 3 [/SUP], Fuming Zhang[SUP] 4 [/SUP], Vitor H Pomin[SUP] 5 [/SUP], Nicole M Ashpole[SUP] 5 [/SUP], Dipanwita Mitra[SUP] 1 [/SUP], Martin G McCandless[SUP] 1 [/SUP], Weihua Jin[SUP] 4 [/SUP], Hao Liu[SUP] 5 [/SUP], Poonam Sharma[SUP] 1 [/SUP], Robert J Linhardt[SUP] 6 [/SUP]
Affiliations
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. Like other betacoronaviruses, attachment and entry of SARS-CoV-2 is 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 anti-viral 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 an IC[SUB]50[/SUB] of 5.99 μg/L, 1.08 mg/L, 1.77 μg/L, and 5.86 mg/L 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 recent 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 anti-viral 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.
. 2020 Nov 10;JVI.01987-20.
doi: 10.1128/JVI.01987-20. Online ahead of print.
Effective Inhibition of SARS-CoV-2 Entry by Heparin and Enoxaparin Derivatives
Ritesh Tandon[SUP] 1 [/SUP], Joshua S Sharp[SUP] 2 3 [/SUP], Fuming Zhang[SUP] 4 [/SUP], Vitor H Pomin[SUP] 5 [/SUP], Nicole M Ashpole[SUP] 5 [/SUP], Dipanwita Mitra[SUP] 1 [/SUP], Martin G McCandless[SUP] 1 [/SUP], Weihua Jin[SUP] 4 [/SUP], Hao Liu[SUP] 5 [/SUP], Poonam Sharma[SUP] 1 [/SUP], Robert J Linhardt[SUP] 6 [/SUP]
Affiliations
- PMID: 33173010
- DOI: 10.1128/JVI.01987-20
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. Like other betacoronaviruses, attachment and entry of SARS-CoV-2 is 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 anti-viral 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 an IC[SUB]50[/SUB] of 5.99 μg/L, 1.08 mg/L, 1.77 μg/L, and 5.86 mg/L 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 recent 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 anti-viral 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.