CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(06): 984-997
DOI: 10.1055/a-1807-0168
Blood Cells, Inflammation and Infection

Pentosan Polysulfate Inhibits Attachment and Infection by SARS-CoV-2 In Vitro: Insights into Structural Requirements for Binding

Sabrina Bertini*
1   Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Milan, Italy
,
Anna Alekseeva*
2   Centro Alta Tecnologia “Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni” Srl, Milan, Italy
,
Stefano Elli*
1   Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Milan, Italy
,
Isabel Pagani*
3   Viral Pathogenesis and Biosafety Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
,
Serena Zanzoni*
4   Centro Piattaforme Tecnologiche, University of Verona, Verona, Italy
,
Giorgio Eisele
2   Centro Alta Tecnologia “Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni” Srl, Milan, Italy
,
Ravi Krishnan
5   Paradigm Biopharmaceuticals Ltd., Melbourne, Victoria, Australia
,
Klaus P. Maag
6   Bene PharmaChem GmbH & Co.KG, Geretsried, Germany
,
Christian Reiter
5   Paradigm Biopharmaceuticals Ltd., Melbourne, Victoria, Australia
,
Dominik Lenhart
6   Bene PharmaChem GmbH & Co.KG, Geretsried, Germany
,
Rudolf Gruber
6   Bene PharmaChem GmbH & Co.KG, Geretsried, Germany
,
Edwin A Yates*
7   Department of Biochemistry and Systems Biology, ISMIB, University of Liverpool, Liverpool, United Kingdom
,
Elisa Vicenzi*
3   Viral Pathogenesis and Biosafety Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
,
Annamaria Naggi**
1   Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Milan, Italy
,
Antonella Bisio**
1   Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Milan, Italy
,
Marco Guerrini**
1   Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Milan, Italy
› Author Affiliations
Funding None.

Abstract

Two years since the outbreak of the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 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 nuclear magnetic resonance spectroscopy and liquid chromatography–mass spectrometry, 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 in 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.

* Joint first authors.


** Senior authors.


Supplementary Material



Publication History

Received: 03 January 2021

Accepted: 03 March 2022

Accepted Manuscript online:
23 March 2022

Article published online:
04 July 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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