Abstract
With the increased prevalence of new SARS-CoV-2 variants of concern, such as Delta and Omicron, the COVID-19 pandemic has become an ongoing human health disaster, killing millions worldwide. SARS-CoV-2 invades its host through the interaction of its spike (S) protein with a host cell receptor, angiotensin-converting enzyme 2 (ACE2). In addition, heparan sulfate (HS) on the surface of host cells plays an important role as a co-receptor for this viral pathogen–host cell interaction. Our previous studies demonstrated that many sulfated glycans, such as heparin, fucoidans, and rhamnan sulfate have anti-SARS-CoV-2 activities. In the current study, a small library of sulfated glycans and highly negatively charged compounds, including pentosan polysulfate (PPS), mucopolysaccharide polysulfate (MPS), sulfated lactobionic acid, sulodexide, and defibrotide, was assembled and evaluated for binding to the S-proteins and inhibition of viral infectivity in vitro. These compounds inhibited the interaction of the S-protein receptor-binding domain (RBD) (wild type and different variants) with immobilized heparin, a highly sulfated HS, as determined using surface plasmon resonance (SPR). PPS and MPS showed the strongest inhibition of interaction of heparin and S-protein RBD. The competitive binding studies showed that the IC50 of PPS and MPS against the S-protein RBD binding to immobilized heparin was ~35 nM and ~9 nM, respectively, much lower than the IC50 for soluble heparin (IC50 = 56 nM). Both PPS and MPS showed stronger inhibition than heparin on the S-protein RBD or spike pseudotyped lentiviral particles binding to immobilized heparin. Finally, in an in vitro cell-based assay, PPS and MPS exhibited strong antiviral activities against pseudotyped viral particles of SARS-CoV-2 containing wild-type or Delta S-proteins.
Highlights
The ongoing COVID-19 pandemic, caused by acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), has resulted in a public health disaster and led to millions of deaths globally
We demonstrated previously [22] that heparin interacts with the SARS-CoV-2 S-protein with high avidity and proposed that heparan sulfate (HS) facilitates host cell entry of SARS-CoV-2 as a coreceptor of angiotensin-converting enzyme 2 (ACE2), which has been confirmed by other researchers [23,24]
The competitive binding studies revealed that the IC50 of pentosan polysulfate (PPS) and mucopolysaccharide polysulfate (MPS) against the S-protein receptor-binding domain (RBD) binding to immobilized heparin was ~35 nM and ~9 nM, respectively, which was much lower than the IC50 for heparin (IC50 = 56 nM)
Summary
The ongoing COVID-19 pandemic, caused by acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), has resulted in a public health disaster and led to millions of deaths globally. Health Organization (Alpha, Beta, Gamma, Delta, Omicron, etc.) since the beginning of the pandemic. These variants of concern (VOC) have exhibited increased transmissibility, Pharmaceuticals 2022, 15, 258. Pharmaceuticals 2022, 15, 258 virulence, and/or a reduced effectiveness of vaccines, resulting in immune breakthrough infections [1,2,3]. Supplementing vaccines, some oral or injectable therapeutics have been developed (or repurposed), including remdesivir, favipiravir, simeprevir, various monoclonal antibodies, and most recently paxlovid and molnupiravir, which can inhibit the infection or propagation of SARS-CoV-2 [8,9]. New effective drugs for both therapeutic and critically prophylactic uses to combat COVID-19 are desperately needed
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