Abstract
This study highlights the roles of pentosan polysulfate as a decoy anti-viral prophylactic that prevents severe acute respiratory syndrome coronavirus-2 infection. PPS also has multifunctional cell and tissue protective properties relevant to the treatment of the symptoms produced by long COVID disease. PPS has heparan sulfate (HS)-like properties, a key functional component of the lung glycocalyx. The glycocalyx is also rich in hyaluronan which has important cell shielding and cell regulatory properties. A healthy glycocalyx prevents access of viral particles to cell surface heparan sulfate-proteoglycans (syndecan, glypican) which act as viral receptors. Pentosan polysulfate promotes hyaluronan synthesis by many cell types, ensuring cells are surrounded by a healthy protective glycocalyx. Hyaluronan, however, has a relatively short biological half-life and is susceptible to degradation by hyaluronidases that are upregulated by inflammatory cytokines in acute respiratory distress syndrome in COVID-19 disease. This results in the glycocalyx becoming degraded and endothelial cells dysfunctional in COVID-19 disease. Prevention of viral interaction with the host cell surface intercepted by pentosan polysulfate, a decoy viral binding prophylactic agent, blocks viral interaction with cell-surface heparan sulfate, preventing viral interactions with other cell surface receptors such as neuropilin-1 and angiotensin-converting enzyme 2. Co-operation between heparan sulfate, neuropilin-1 and angiotensin-converting enzyme 2 facilitates the infection of host cells with severe acute respiratory syndrome coronavirus 2, thus if the initial interaction with heparan sulfate is blocked this prevents the subsequent viral interactive stages. Pentosan polysulfate also has multifunctional cell and tissue protective properties, broad anti-oxidant and anti-inflammatory properties and inhibits cytokine production in acute respiratory disease syndrome. Pentosan polysulfate inhibits p38 mitogen-activated protein kinase and nuclear factor-κB activation, reducing the production of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β and interleukin-6. Furthermore, pentosan polysulfate is processed by enzymes of the gut microbiome into prebiotic xylo-oligosaccharides that preserve gut health and combat gut dysbiosis seen in COVID-19 disease. Studies are thus warranted to fully assess pentosan polysulfate as an anti-severe acute respiratory syndrome coronavirus-2 prophylactic agent and its multifunctional cell and tissue protective properties. Furthermore, from a practical and economic point of view, treatment with pentosan polysulfate would offer substantial cost-benefit advantages over conventional vaccine and antibiotic treatments and could also be used in an adjunctive capacity with existing therapies, offering flexibility in its use.