Anti-SARS-CoV-2 and anticoagulant properties of <i>Pentacta pygmaea</i> fucosylated chondroitin sulfate depend on high molecular weight structures

Dwivedi, Rohini; Sharma, Poonam; Eilts, Friederike; Zhang, Fuming; Linhardt, Robert J.; Tandon, Ritesh; Pomin, Vitor H.

doi:10.1093/glycob/cwac063

Cited by 11 publications

(42 citation statements)

References 24 publications

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“…5) are consistent with a mechanism in which MSGs inhibit virion attachment by binding to spike and thereby competitively inhibiting spike from interacting with www.nature.com/scientificreports/ cell-surface HS. This mechanism is further supported by previously published studies that used surface plasmon resonance spectroscopy to demonstrate that MSGs can bind with high affinity to various coronaviral spike protein variants and competitively inhibit heparin binding 22,31,44 . While we have not directly examined MSGs for potential virucidal effects, virucidal effects of MSG are rare in general 45 and the mechanism by which heparin and other sulfonated compounds inhibit SARS-CoV-2 specifically has been reported to be non-virucidal 46 .…”

Section: Discussionsupporting

confidence: 64%

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Antiviral activity of marine sulfated glycans against pathogenic human coronaviruses

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Dwivedi

Kim

et al. 2023

Sci Rep

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Great interest exists towards the discovery and development of broad-spectrum antivirals. This occurs due to the frequent emergence of new viruses which can also eventually lead to pandemics. A reasonable and efficient strategy to develop new broad-spectrum antivirals relies on targeting a common molecular player of various viruses. Heparan sulfate is a sulfated glycosaminoglycan present on the surface of cells which plays a key role as co-receptor in many virus infections. In previous work, marine sulfated glycans (MSGs) were identified as having antiviral activities. Their mechanism of action relies primarily on competitive inhibition of virion binding to heparan sulfate, preventing virus attachment to the cell surface prior to entry. In the current work we used pseudotyped lentivirus particles to investigate in a comparative fashion the inhibitory properties of five structurally defined MSGs against SARS-CoV-1, SARS-CoV-2, MERS-CoV, and influenza A virus (IAV). MSGs include the disaccharide-repeating sulfated galactan from the red alga Botryocladia occidentalis, the tetrasaccharide-repeating sulfated fucans from the sea urchin Lytechinus variegatus and from the sea cucumber Isostichopus badionotus, and the two marine fucosylated chondroitin sulfates from the sea cucumbers I. badionotus and Pentacta pygmaea. Results indicate specificity of action against SARS-CoV-1 and SARS-CoV-2. Curiously, the MSGs showed decreased inhibitory potencies against MERS-CoV and negligible action against IAV. Among the five MSGs, the two sulfated fucans here studied deserve further attention since they have the lowest anticoagulant effects but still present potent and selective antiviral properties.

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Section: Discussionsupporting

confidence: 64%

“…The anti-SARS-CoV-2 activity of BoSG, LvSF, IbSF, IbFucCS, and PpFucCS have been previously described using a pseudotyped baculoviral system 22,31,44 . The results demonstrate that these two FucCS are equally the most active of the MSGs, followed by BoSG, heparin, and IbSF, which were comparable to LvSF, the least active compounds (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Antiviral activity of marine sulfated glycans against pathogenic human coronaviruses

Zoepfl

Dwivedi

Kim

et al. 2023

Sci Rep

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“…It was rapidly determined that heparin was capable of inhibiting SARS-CoV-2 infection of cells by competing with HS for binding to the spike protein [ 10 ]. There is no evidence for selectivity for any HS structural motif [ 77 ], and indeed numerous different sulphated polymers have been shown to compete with HS binding to SARS-CoV-2 spike protein including marine sulphated glycans [ 78 , 79 ], pentosan polysulphate (a semi-synthetic sulphated xylan) [ 51 ] and others [ 80 ].…”

Section: Non-anticoagulant Action Of Heparin and Sepsismentioning

confidence: 99%

Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment

Hogwood

Gray

2023

Pharmaceuticals

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Sepsis is a life-threatening hyperreaction to infection in which excessive inflammatory and immune responses cause damage to host tissues and organs. The glycosaminoglycan heparan sulphate (HS) is a major component of the cell surface glycocalyx. Cell surface HS modulates several of the mechanisms involved in sepsis such as pathogen interactions with the host cell and neutrophil recruitment and is a target for the pro-inflammatory enzyme heparanase. Heparin, a close structural relative of HS, is used in medicine as a powerful anticoagulant and antithrombotic. Many studies have shown that heparin can influence the course of sepsis-related processes as a result of its structural similarity to HS, including its strong negative charge. The anticoagulant activity of heparin, however, limits its potential in treatment of inflammatory conditions by introducing the risk of bleeding and other adverse side-effects. As the anticoagulant potency of heparin is largely determined by a single well-defined structural feature, it has been possible to develop heparin derivatives and mimetic compounds with reduced anticoagulant activity. Such heparin mimetics may have potential for use as therapeutic agents in the context of sepsis.

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“…The challenge comes from the fact that this class of molecules, e.g., heparin ( Fig 1A ), are endowed with potential anticoagulant effects, which might pose bleeding or hemorrhagic risks during their clinical administration as antivirals [ 15 – 18 ]. Recently, however, we were able to present an efficient strategy to increase selectivity of action by dissociating the anti-SARS-CoV-2 and anticoagulant activities of two different marine sulfated glycans (MSGs): one sulfated galactan from the red alga, Botryocladia occidentalis [ 12 ], and one fucosylated chondroitin sulfate (FucCS) from the sea cucumber, Pentacta pygmaea (PpFucCS) ( Fig 1B ) [ 19 ]. This strategy relies on a chemical depolymerization process of these MSGs using a controlled hydrolysis.…”

Section: Introductionmentioning

confidence: 99%

“…This strategy relies on a chemical depolymerization process of these MSGs using a controlled hydrolysis. Since the anticoagulant activity of MSGs are known to be generally molecular weight (MW)-dependent [ 20 , 21 ], oligosaccharides of lower MWs than the native molecules can eventually lead to reduced anticoagulant properties with little or no impact on the potency or efficacy of the antiviral response [ 12 , 19 ]. Since each MSG has its own structure and can present different levels of anticoagulant versus anti-SARS-CoV-2 activities, we believe that each MSG can respond differently to the applied chemical strategy of depolymerization for segregation of the two biological activities.…”

Section: Introductionmentioning

confidence: 99%

Structural requirements of Holothuria floridana fucosylated chondroitin sulfate oligosaccharides in anti-SARS-CoV-2 and anticoagulant activities

et al. 2023

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Fucosylated chondroitin sulfate (FucCS) is a unique glycosaminoglycan found primarily in sea cucumbers. This marine sulfated glycan is composed of a chondroitin sulfate backbone decorated with fucosyl branches attached to the glucuronic acid. FucCS exhibits potential biological actions including inhibition of blood clotting and severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection. These biological effects have been attributed to certain structural features, including molecular weight (MW), and/or those related to fucosylation, such as degrees of fucosyl branches, sulfation patterns and contents. In a previous work, we were able to generate oligosaccharides of the FucCS from Pentacta pygmaea (PpFucCS) with reduced anticoagulant effect but still retaining significant anti-SARS-CoV-2 activity against the delta strain. In this work, we extended our study to the FucCS extracted from the species Holothuria floridana (HfFucCS). The oligosaccharides were prepared by free-radical depolymerization of the HfFucCS via copper-based Fenton reaction. One-dimensional 1H nuclear magnetic resonance spectra were employed in structural analysis. Activated partial thromboplastin time and assays using protease (factors Xa and IIa) and serine protease inhibitors (antithrombin, and heparin cofactor II) in the presence of the sulfated carbohydrates were used to monitor anticoagulation. Anti-SARS-CoV-2 effects were measured using the concentration–response inhibitory curves of HEK-293T-human angiotensin-converting enzyme-2 cells infected with a baculovirus pseudotyped SARS-CoV-2 wild-type and delta variant spike (S)-proteins. Furthermore, the cytotoxicity of native HfFucCS and its oligosaccharides was also assessed. Like for PpFucCS, we were able to generate a HfFucCS oligosaccharide fraction devoid of high anticoagulant effect but still retaining considerable anti-SARS-CoV-2 actions against both variants. However, compared to the oligosaccharide fraction derived from PpFucCS, the average MW of the shortest active HfFucCS oligosaccharide fraction was significantly lower. This finding suggests that the specific structural feature in HfFucCS, the branching 3,4-di-sulfated fucoses together with the backbone 4,6-di-sulfated N-acetylgalactosamines, is relevant for the anti-SARS-CoV-2 activity of FucCS molecules.

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Anti-SARS-CoV-2 and anticoagulant properties of Pentacta pygmaea fucosylated chondroitin sulfate depend on high molecular weight structures

Cited by 11 publications

References 24 publications

Antiviral activity of marine sulfated glycans against pathogenic human coronaviruses

Antiviral activity of marine sulfated glycans against pathogenic human coronaviruses

Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment

Structural requirements of Holothuria floridana fucosylated chondroitin sulfate oligosaccharides in anti-SARS-CoV-2 and anticoagulant activities

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