Fractionation of sulfated galactan from the red alga Botryocladia occidentalis separates its anticoagulant and anti-SARS-CoV-2 properties

Abstract

Sulfation pattern and molecular weight (MW) play a key role in the biological actions of sulfated glycans. Besides anticoagulant effects, certain sulfated glycans can also exhibit anti-SARS-CoV-2 properties. To develop a more selective antiviral carbohydrate, an efficient strategy to separate these two actions is required. In this work, low MW fractions derived from the red alga Botryocladia occidentalis sulfated galactan (BoSG) were generated, structurally characterized, and tested for activity against SARS-CoV-2 and blood coagulation. The lowest MW fraction was found to be primarily composed of octasaccharides of monosulfated monosaccharides. Unlike heparin or native BoSG, we found that hydrolyzed BoSG products had weak anticoagulant activities as seen by aPTT and inhibitory assays using purified cofactors. In contrast, lower MW BoSG-derivatives retained anti-SARS-CoV-2 activity using SARS-CoV-2 spike (S)-protein pseudotyped lentivirus vector in HEK-293T-hACE2 cells monitored by GFP. Surface plasmon resonance confirmed that longer chains are necessary for BoSG to interact with coagulation cofactors but is not required for interactions with certain S-protein variants. We observed distinct affinities of BoSG derivatives for the S-proteins of different SARS-CoV-2 strains, including WT, N501Y (Alpha), K417T/E484K/N501Y (Gamma), and L542R (Delta) mutants, and stronger affinity for the N501Y-containing variants. Docking of the four possible monosulfated BoSG disaccharides in interactions with the N501Y mutant S-protein predicted potential binding poses of the BoSG constructs and favorable binding in close proximity to the 501Y residue. Our results demonstrate that depolymerization and fractionation of BoSG are an effective strategy to segregate its anticoagulant property from its anti-SARS-CoV-2 action. Sulfation pattern and molecular weight (MW) play a key role in the biological actions of sulfated glycans. Besides anticoagulant effects, certain sulfated glycans can also exhibit anti-SARS-CoV-2 properties. To develop a more selective antiviral carbohydrate, an efficient strategy to separate these two actions is required. In this work, low MW fractions derived from the red alga Botryocladia occidentalis sulfated galactan (BoSG) were generated, structurally characterized, and tested for activity against SARS-CoV-2 and blood coagulation. The lowest MW fraction was found to be primarily composed of octasaccharides of monosulfated monosaccharides. Unlike heparin or native BoSG, we found that hydrolyzed BoSG products had weak anticoagulant activities as seen by aPTT and inhibitory assays using purified cofactors. In contrast, lower MW BoSG-derivatives retained anti-SARS-CoV-2 activity using SARS-CoV-2 spike (S)-protein pseudotyped lentivirus vector in HEK-293T-hACE2 cells monitored by GFP. Surface plasmon resonance confirmed that longer chains are necessary for BoSG to interact with coagulation cofactors but is not required for interactions with certain S-protein variants. We observed distinct affinities of BoSG derivatives for the S-proteins of different SARS-CoV-2 strains, including WT, N501Y (Alpha), K417T/E484K/N501Y (Gamma), and L542R (Delta) mutants, and stronger affinity for the N501Y-containing variants. Docking of the four possible monosulfated BoSG disaccharides in interactions with the N501Y mutant S-protein predicted potential binding poses of the BoSG constructs and favorable binding in close proximity to the 501Y residue. Our results demonstrate that depolymerization and fractionation of BoSG are an effective strategy to segregate its anticoagulant property from its anti-SARS-CoV-2 action. A global pandemic caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) or coronavirus disease-19 (Covid-19) was declared by the World Health Organization in March 2020 (1Peng M. Outbreak of COVID-19: An emerging global pandemic threat.Biomed. Pharmacother. 2020; 129: 110499Crossref PubMed Scopus (20) Google Scholar). The virus has rapidly spread to more than 222 countries since February 2020. SARS-CoV-2 is a zoonotic beta coronavirus primarily transmitted from person-to-person through respiratory droplets (2Stadnytskyi V. Bax C.E. Bax A. Anfinrud P. The airborne lifetime of small speech droplets and their potential importance in SARS-CoV-2 transmission.Proc. Natl. Acad. Sci. U. S. A. 2020; 117: 11875-11877Crossref PubMed Scopus (512) Google Scholar, 3Echternach M. Gantner S. Peters G. 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R. activities of four sulfated glycans against and 2021; PubMed Scopus Google but also J. sulfated activity and of red blood cell by PubMed Scopus Google anticoagulant sulfated glycans with anticoagulant PubMed Scopus Google Scholar, An sulfated galactan has an to of and of the coagulation PubMed Scopus Google Scholar, and anticoagulant activity of a sulfated galactan from the red a for the anticoagulant PubMed Scopus Google Scholar, and anticoagulant activity of sulfated PubMed Scopus Google and An sulfated galactan has an to of and of the coagulation PubMed Scopus Google Scholar, anticoagulant activity of sulfated PubMed Scopus Google Scholar, the of sulfated of PubMed Scopus Google BoSG is structurally in of its composed of the but in of pattern The anticoagulant and of BoSG have been and have been observed in these R. 2020; Scopus Google Scholar, F. M. from the and Scopus (20) Google Scholar, the of sulfated from as a of new PubMed Scopus Google Scholar). mechanism of have activity heparin and and of molecular weight (MW) these activities and anticoagulant activity of a sulfated galactan from the red a for the anticoagulant PubMed Scopus Google Scholar, and anticoagulant activity of sulfated PubMed Scopus Google Scholar, anticoagulant activity of sulfated PubMed Scopus Google Scholar). we the and of BoSG and its low MW a was through and including plasmon resonance and assays inhibitory activities against blood cofactors or entry by Our results demonstrate that we can sulfated from a alga with low of anticoagulant activity anti-SARS-CoV-2 were from the of the red alga B. occidentalis through using by as and anticoagulant activity of sulfated PubMed Scopus Google Scholar, S. The activities of and PubMed Scopus Google Scholar, by with J. 49: PubMed Scopus Google Scholar). 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The native BoSG, a hydrolyzed BoSG and the four fractions of different derived from BoSG were to in anticoagulant assays to the of MW the anticoagulant of The were the and protease assays using purified and and the blood and and with anticoagulant activity of was in as a activities of the BoSG from the aPTT as well as the inhibitory from the inhibitory are in anticoagulant of BoSG and derivatives through of coagulation and by or heparin in the of different sulfated were using a were using a in a new the in anticoagulant can be seen for native BoSG is than BoSG is in anticoagulant the anticoagulant of BoSG were of activity with the hydrolyzed The derivatives with different activity as the MW and results that the anticoagulant of BoSG is and the native MW is for its anticoagulant action. of BoSG to lower MW an efficient strategy to the anticoagulant of this The anti-SARS-CoV-2 activities of BoSG, and derivatives and were by in protein of cells with a lentivirus pseudotyped with SARS-CoV-2 S-protein effective from the of are in be with but in a anti-SARS-CoV-2 activities were observed for BoSG and anti-SARS-CoV-2 of and were lower than native BoSG BoSG, and had tested results than native BoSG, low MW BoSG derivatives anti-SARS-CoV-2 of by a lentivirus pseudotyped with SARS-CoV-2 from from in a new using heparin a was to the binding of BoSG, and low MW derivatives with blood coagulation and and four S-protein including N501Y and K417T/E484K/N501Y activities were to the protein the native BoSG and are in these BoSG has affinity for and but low affinity for as and anticoagulant activity of sulfated PubMed Scopus Google Scholar, the of sulfated of PubMed Scopus Google Scholar). low MW derivatives of BoSG and binding to the blood is with the of anticoagulant activity of BoSG derivatives seen in for of binding by coagulation or S-proteins to from from from in a new The binding of native BoSG to the four S-protein was in to that observed for heparin is with the anti-SARS-CoV-2 in the BoSG low MW and distinct binding the was to interact with but with different of affinity The affinity was observed for the mutant binding affinity for the N501Y mutant some affinity for the K417T/E484K/N501Y mutant and weak binding to and the mutant results that the BoSG derivatives have affinity for the that the N501Y In through the is also that the native BoSG has stronger binding affinities for the N501Y-containing than for the mutant or The binding affinities of BoSG to the and variants were than of To the of different BoSG to binding with the S-protein four possible BoSG disaccharides were and to the binding close to the N501Y in which had the affinity observed by A heparin was also and for The binding in this was the for the sulfated glycans in binding to the and the N501Y mutant S-protein R. P. P. F. P. R. and of sulfated glycans potential for SARS-CoV-2 2021; PubMed Scopus Google Scholar). The are in and of the poses for the heparin and the four BoSG disaccharides from are in The of the heparin to the N501Y mutant S-protein that its is and its and interact with and binding to the N501Y mutant with A binding was observed for the BoSG some as and were not seen to be with the BoSG in a of the as to that of the heparin The BoSG disaccharides and a binding but that from the heparin and BoSG binding In the BoSG a with of its which the An the of the and was and interactions with and of the of the the with of the in BoSG in and and in and In the BoSG the in the two with and The and interactions with and of the to was found for the BoSG an with the of the An was observed and the of the of this for the BoSG the and of the interactions with and The of the interactions with and The of this BoSG two key interactions of the and with and the two BoSG disaccharides in the and the binding of the was with the by the of the from the poses of the be seen that and play key in binding with the S-protein N501Y and the sulfated galactan from the red alga B. occidentalis (BoSG) are in highly in and anticoagulant activity of sulfated PubMed Scopus Google Scholar, anticoagulant activity of sulfated PubMed Scopus Google Scholar, the of sulfated of PubMed Scopus Google Scholar, R. P. of sulfated from the red Botryocladia occidentalis and PubMed Scopus Google Scholar, from the sulfated galactan from the alga J. 2020; PubMed Scopus (2) Google Scholar, activity of a sulfated and with PubMed Scopus Google Scholar, galactan is a of of PubMed Scopus Google and An sulfated galactan has an to of and of the coagulation PubMed Scopus Google Scholar, the of sulfated of PubMed Scopus Google Scholar, in of for in their anticoagulant and PubMed Scopus Google can also potential F. F. sulfated galactan and cells from and (Basel). 2021; PubMed Scopus Google Scholar, J. sulfated activity and of red blood cell by PubMed Scopus Google Scholar, from the sulfated galactan from the alga J. 2020; PubMed Scopus (2) Google including F. F. sulfated galactan and cells from and (Basel). 2021; PubMed Scopus Google Scholar). In the of BoSG is not with to its highly of disaccharides with and but in of Sulfation can different of this and of the and and of the and different and of BoSG and We to the strategy of BoSG for the of to the the and of to this are not are and for sulfated as sulfated and anticoagulant activity of a sulfated of a from the by of and heparin anticoagulant 15: PubMed Scopus Google Scholar, of sulfated A selective and an for sulfated 15: PubMed Scopus Google Scholar, from the and but different Google Scholar, of pattern the and of sulfated as by and PubMed Scopus Google Scholar, of and the of the sulfated from 2020; PubMed Scopus Google and also for BoSG anticoagulant activity of sulfated PubMed Scopus Google we to for depolymerization of The were for BoSG was to with different The MW of this from to and fractionation to a with and a of or of of BoSG during the In the of the was observed during the as from using and and of BoSG during of low MW by was not since selective the has been during of sulfated glycans and anticoagulant activity of a sulfated of a from the by of and heparin anticoagulant 15: PubMed Scopus Google Scholar, of sulfated A selective and an for sulfated 15: PubMed Scopus Google Scholar). the four fractions of BoSG were and as the the lowest MW in which the has a of and in was through the of the and of a monosulfated The of the of the is close in the The of the of the was in the a of the of this from is the of the of with and of the of and the of are the of we were to demonstrate the of the BoSG is composed of more than different to also with different and be in future the development of a structurally as an anti-SARS-CoV-2 have that BoSG is in the coagulation by the inhibitory activities of and and and anticoagulant activity of a sulfated galactan from the red a for the anticoagulant PubMed Scopus Google Scholar, and anticoagulant activity of sulfated PubMed Scopus Google Scholar, anticoagulant activity of sulfated PubMed Scopus Google Scholar). we these anticoagulant using the BoSG low MW derivatives and We observed a the MW of BoSG in In the native BoSG was of of coagulation activities in assays purified and The BoSG derivatives activity in the aPTT these were observed to be the mechanism the activity observed through aPTT is to the anticoagulant of BoSG, as sulfated glycans with anticoagulant PubMed Scopus Google Scholar, the of sulfated of PubMed Scopus Google Scholar, activity of a sulfated and with PubMed Scopus Google Scholar). the anticoagulant of low MW BoSG is of anticoagulant be in these to and in The weak anticoagulant of sulfated glycans as antiviral can be by of as for to be necessary for the of BoSG their anticoagulant activity is is that not aPTT and not as a to which not We that the BoSG their low aPTT future in be to A the for the of longer chains of BoSG to the anticoagulant anticoagulant activity of sulfated PubMed Scopus Google Scholar). have that the mechanism is more than the mechanism in and that longer BoSG chains are to or and or in the of this has the its activity the coagulation with of the anticoagulant anticoagulant activity of sulfated PubMed Scopus Google Scholar). we demonstrate that in MW of BoSG its anticoagulant through the In contrast, of the MW of BoSG not anti-SARS-CoV-2 activity and than native BoSG, which is composed of octasaccharides and monosulfated was in the entry of SARS-CoV-2 and were and than native that a BoSG be for of S-protein with or Our binding results have confirmed that of MW of BoSG can the anticoagulant but not the anti-SARS-CoV-2 the of the biological since MW we also during of The distinct of these two and can be by the results from the of the BoSG derivatives and the inhibitory and and can be is in since these derivatives the than the native BoSG, especially the the of the are in the in and in these more with to MW than to The MW from native BoSG to the MW of to the anticoagulant property and in and but not anti-SARS-CoV-2 activity and and a MW for the The anti-SARS-CoV-2 activities of and sulfated as to which in these fractions are primarily MW than were and of MW or In contrast, the anticoagulant of BoSG longer chains to the anticoagulant mechanism seen in the In longer BoSG chains can and of blood by the to the anticoagulant that of heparin binding by S-protein the N501Y can be by in to effective molecular interactions and Docking of the BoSG disaccharides to the N501Y mutant S-protein the poses of the BoSG derivatives in the binding close to the 501Y and the possible the S-protein for potential to of the sulfated glycans that binding to the close to the 501Y was Docking has that heparin and the BoSG can interact with the S-protein N501Y with binding poses A and but with different poses as with the BoSG which binding poses the two interactions were observed and with the A and the BoSG interactions were observed and and the The BoSG disaccharides the the and had the than the In and the binding of heparin and BoSG to the S-protein the 501Y residue. In this work, we were to a of different fractions from the structurally sulfated galactan from the red alga B. occidentalis BoSG anticoagulant and anti-SARS-CoV-2 The sulfated glycans be activity coagulation. the more its antiviral action. a strategy of we were to the anticoagulant of the but the anti-SARS-CoV-2 action. we also of the BoSG and low MW derivatives the SARS-CoV-2 variants that the N501Y in their S-protein In the of anticoagulant with anti-SARS-CoV-2 the and selective of the red sulfated

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