Pentosan polysulfate inhibits attachment and infection by SARS-CoV-2 in vitro : insights into structural requirements for binding
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Abstract
Two years since the outbreak of the novel coronavirus SARS-CoV-2 pandemic, there remain few clinically effective drugs to complement vaccines. One is the anticoagulant, heparin, which in 2004 was found able to inhibit invasion of SARS CoV (CoV-1) and which has been employed during the current pandemic to prevent thromboembolic complications and moderate potentially damaging inflammation. Heparin has also been shown experimentally to inhibit SARS-CoV-2 attachment and infection in susceptible cells. At high therapeutic doses however, heparin increases the risk of bleeding and prolonged use can cause heparin-induced thrombocytopenia, a serious side-effect. One alternative, with structural similarities to heparin is the plant-derived, semi-synthetic polysaccharide, pentosan polysulfate (PPS). PPS is an established drug for the oral treatment of interstitial cystitis, is well-tolerated and exhibits weaker anticoagulant effects than heparin. In an established Vero cell model, PPS and its fractions of varying molecular weights, inhibited invasion by SARS-CoV-2. Intact PPS and its size-defined fractions were characterized by molecular weight distribution and chemical structure using NMR spectroscopy and LC-MS, then employed to explore the structural basis of interactions with SARS-CoV-2 spike protein receptor-binding domain (S1 RBD) and the inhibition of Vero cell invasion. PPS was as effective as unfractionated heparin, but more effective at inhibiting cell infection than low molecular weight heparin (on a weight/volume basis). Isothermal titration calorimetry and viral plaque-forming assays demonstrated size-dependent binding to S1 RBD and inhibition of Vero cell invasion, suggesting the potential application of PPS as a novel inhibitor of SARS-CoV-2 infection.
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SciScore for 10.1101/2021.12.19.473359: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Vero cell culture and assays: Vero cells were plated at 2.5×105 cell/well in 24-well plates in EMEM supplemented with 10% fetal bovine serum (complete medium). Verosuggested: NoneSoftware and Algorithms Sentences Resources Data were analyzed using Zetasizer software version 7.11 (Malvern Panalytical, Malvern, UK) and each value corresponds to the average of three separate measurements. Zetasizersuggested: NoneStatistical Analysis: Prism GraphPad software v. Prism GraphPadsuggested: NoneThe final conformations of these two xylohexasaccharides having Xyl residues in 1C4 and 4C1 were … SciScore for 10.1101/2021.12.19.473359: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Vero cell culture and assays: Vero cells were plated at 2.5×105 cell/well in 24-well plates in EMEM supplemented with 10% fetal bovine serum (complete medium). Verosuggested: NoneSoftware and Algorithms Sentences Resources Data were analyzed using Zetasizer software version 7.11 (Malvern Panalytical, Malvern, UK) and each value corresponds to the average of three separate measurements. Zetasizersuggested: NoneStatistical Analysis: Prism GraphPad software v. Prism GraphPadsuggested: NoneThe final conformations of these two xylohexasaccharides having Xyl residues in 1C4 and 4C1 were energy minimized using the Maestro 12.7 Macromodel 13.1 software and molecular mechanic Amber* force-field (Suite 2021-1, Schrödinger Inc. San Diego) (Fig. Maestrosuggested: (Maestro, RRID:SCR_016748)The software Autodock 4.2 was used for the automatic docking. Autodocksuggested: (AutoDock, RRID:SCR_012746)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- No funding statement was detected.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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