Non-anticoagulant Heparin as a Pre-exposure Prophylaxis Prevents Lyme Disease Infection

Lin, Yi‐Pin; Yu, Yanlei; Marcinkiewicz, Ashley L.; Lederman, Patricia; Hart, Thomas; Zhang, Fuming; Linhardt, Robert J.

doi:10.1021/acsinfecdis.9b00425

Cited by 12 publications

(9 citation statements)

References 89 publications

(194 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Keratan sulfate (KS) was prepared from bovine cornea as previously described 24 . Non-anticoagulant low molecular weight HP (NACH) was synthesized from dalteparin, a nitrous acid depolymerization product of porcine intestinal HP, followed by periodate oxidation 25 . Non-anticoagulant heparin TriS (NS2S6S) was synthesized from N -sulfo heparosan with subsequent modification with C5-epimerase and 2- O - and 6- O -sulfotransferases (2OST and 6OST1/6OST3) 26 .…”

Section: Methodsmentioning

confidence: 99%

Effective Inhibition of SARS-CoV-2 Entry by Heparin and Enoxaparin Derivatives

Tandon

Sharp

Zhang

et al. 2020

Preprint

Self Cite

119

View full text Add to dashboard Cite

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 IC50 of 599 ng/L, 108 µg/L, 177 ng/L, and 586 µg/L respectively. The low serum bioavailability of intranasally administered UFH, along with data suggesting that the nasal epithelium is a portal for initial infection and transmission, suggest that intranasal administration of UFH may be an effective and safe prophylactic treatment.

show abstract

Section: Methodsmentioning

confidence: 99%

Effective Inhibition of SARS-CoV-2 Entry by Heparin and Enoxaparin Derivatives

Tandon

Sharp

Zhang

et al. 2020

Preprint

Self Cite

119

View full text Add to dashboard Cite

show abstract

“…In addition, RPI-27 and RPI-28 did not show any toxicity using Vero cells using a standard water-soluble tetrazolium salt-1 (WST-1) assay, even at the highest concentrations studied. Moreover, in an in vitro antiviral assays, RPI-28 had an EC 50 of 8.3 ± 4.6 μg/mL (corresponding to approximately 83 nM) [ 6 ], and was more potent than remdesivir (a drug recently approved for emergency use in severe COVID-19 infections), heparin (2.1 μM), chemo-enzymatically synthesized TriS (a non-anticoagulant heparin analog) [ 7 ] (5.0 μM) and non-anticoagulant low molecular weight (LMW) heparin (NACH) [ 8 ] (55 μM). These strong interactions were attributed to multivalent binding between the polysaccharides and the SGPs of viral particles [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

The structure-activity relationship of the interactions of SARS-CoV-2 spike glycoproteins with glucuronomannan and sulfated galactofucan from Saccharina japonica

Jin

Zhang

Mitra

et al. 2020

International Journal of Biological Macromolecules

Self Cite

View full text Add to dashboard Cite

The SARS-CoV-2 spike glycoproteins (SGPs) and human angiotensin converting enzyme 2 (ACE2) are the two key targets for the prevention and treatment of COVID-19. Host cell surface heparan sulfate (HS) is believed to interact with SARS-CoV-2 SGPs to facilitate host cell entry. In the current study, a series of polysaccharides from Saccharina japonica were prepared to investigate the structure-activity relationship on the binding abilities of polysaccharides (oligosaccharides) to pseudotype particles, including SARS-CoV-2 SGPs, and ACE2 using surface plasmon resonance. Sulfated galactofucan (SJ-D-S-H) and glucuronomannan (Gn) displayed strongly inhibited interaction between SARS-CoV-2 SGPs and heparin while showing negligible inhibition of the interaction between SARS-CoV-2 SGPs and ACE2. The IC 50 values of SJ-D-S-H and Gn in blocking heparin SGP binding were 27 and 231 nM, respectively. NMR analysis showed that the structure of SJ-D-S-H featured with a backbone of 1, 3-linked α-L-Fuc p residues sulfated at C4 and C2/C4 and 1, 3-linked α-L-Fuc p residues sulfated at C4 and branched with 1, 6-linked β-D-galacto-biose; Gn had a backbone of alternating 1, 4-linked β-D-GlcA p residues and 1, 2-linked α-D-Man p residues. The sulfated galactofucan and glucuronomannan showed strong binding ability to SARS-CoV-2 SGPs, suggesting that these polysaccharides might be good candidates for preventing and/or treating SARS-CoV-2.

show abstract

“…Among the tested polysaccharides, RPI-27 and RPI-28, complex sulfated polysaccharides (fucoidans) extracted from the seaweed Saccharina japonica 6 , chemo-enzymatically synthesized trisulfated (TriS) heparin 7 , and unfractionated USP-heparin itself were able to compete with heparin for S-protein binding. We selected these compounds along with a non-anticoagulant low molecular weight heparin (NACH) 8 for further study (Fig. 1b ).…”

mentioning

confidence: 99%