Synthesis of Low-Molecular-Weight Fucoidan Analogue and Its Inhibitory Activities against Heparanase and SARS-CoV-2 Infection.

Heparan sulfate (HS) is ubiquitous on cell surfaces and is used as a receptor by many viruses including SARS-CoV-2. However, increased activity of the inflammatory enzyme heparanase (HPSE), which hydrolyses HS, in patients with COVID-19 not only increases the severity of symptoms but also may facilitate the spread of the virus by degrading HS on the cell surface. Therefore, synthetic HPSE blockades, which can bind to SARS-CoV-2 spike protein (SARS-CoV-2-S) and inhibit viral entry, have attracted much attention. This study investigated the development of a new dual-targeting antiviral agent against HPSE and SARS-CoV-2-S using fucoidan as a structural motif. It was found that all-sulfated fucoidan derivative 10, which exhibited the highest binding affinity to SARS-CoV-2-S among 13 derivatives, also showed the highest inhibitory activity against HPSE. Based on this, a newly designed and synthesized fucoidan analogue 16, in which the octyl group of 10 was changed to a cholestanyl group, was found to show higher activity than 10 but did not inhibit factor Xa associated with undesired anticoagulant effects. The binding affinity of 16 to SARS-CoV-2-S was significantly increased approximately 400-fold over that of 10. Furthermore, 16 effectively inhibited infection by the SARS-CoV-2 Wuhan strain and two Omicron subvariants.

Synthesis of low-molecular weight fucoidan derivatives and their binding abilities to SARS-CoV-2 spike proteins.

Fucoidan derivatives 10-13, whose basic sugar chains are composed of repeating α(1,4)-linked l-fucopyranosyl residues with different sulfation patterns, were designed and systematically synthesized. A structure-activity relationship (SAR) study examined competitive inhibition by thirteen fucoidan derivatives against heparin binding to the SARS-CoV-2 spike (S) protein. The results showed for the first time that 10 exhibited the highest inhibitory activity of the fucoidan derivatives used. The inhibitory activity of 10 was much higher than that of fondaparinux, the reported ligand of SARS-CoV-2 S protein. Furthermore, 10 exhibited inhibitory activities against the binding of heparin with several mutant SARS-CoV-2 S proteins, but was found to not inhibit factor Xa (FXa) activity that could otherwise lead to undesirable anticoagulant activity.

Coacervation in Cationic Polyelectrolyte Solutions with Anionic Amino Acid Surfactants.

Coacervates formed by cationic polyelectrolytes and anionic surfactants are utilized to improve the user's tactile perception of shampooing hair during washing and after drying. In this study, we investigated the formation and structure of coacervates in aqueous systems containing anionic amino acid surfactants. The phase behaviors at constant temperature were investigated in aqueous systems combining cationic polyelectrolyte JR-400 with potassium cocoyl glutamate (CoGluK) or potassium cocoyl glycinate (CoGlyK) for a qualitative depiction of coacervate formation. The composition range of coacervate formation varied with the hydrophilic group of the surfactant. The surface tension was measured at different surfactant concentrations and constant polyelectrolyte concentration. The surface tension behavior revealed the critical association concentrations and critical micelle concentrations, indicating that coacervate was produced via complex formation through electrostatic interaction between opposite charges. Optical microscopy and small-angle X-ray scattering measurements revealed that the coacervates were composed of fibrous aggregates, a few microns thick, and those formed in the CoGlyK system had thicker fibers.

Novel hemagglutinin-binding sulfated oligofucosides and their effect on influenza virus infection.

Among a series of chemically synthesized fucoidan derivatives (1-9), 5 was found for the first time to bind to influenza virus hemagglutinins (HAs) and inhibit hemagglutination activity. In addition, a designed C3-symmetric tripodal ligand 10, synthesized with three sulfated oligofucoside moieties of 5, exhibited much greater hemagglutination inhibition activity than 5. A plaque assay using MDCK cells demonstrated that 10 effectively inhibited influenza virus infection.