Mitoxantrone modulates a heparan sulfate-spike complex to inhibit SARS-CoV-2 infection

Zhang, Qi; Radvák, Peter; Lee, Juhyung; Xu, Yue; Cao-Dao, Vivian; Xu, Miao; Zheng, Wei; Chen, Catherine Z.; Xie, Hang; Ye, Yihong

doi:10.1038/s41598-022-10293-x

Cited by 11 publications

(10 citation statements)

References 42 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We therefore tested whether these latter four anthracyclines also inhibit SARS-CoV-2 infection. Mitoxantrone is an anthraquinone, has similar molecular structure to daunorubicin, previously reported to inhibit SARS-CoV-2 entry (44, 45), and is thus tested as a control (Fig. 5A).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Anthracyclines inhibit SARS-CoV-2 infection

Wang

Pan²,

Ma³

et al. 2023

Preprint

View full text Add to dashboard Cite

Vaccines and drugs are two effective medical interventions to mitigate SARS-CoV-2 infection. Three SARS-CoV-2 inhibitors, remdesivir, paxlovid, and molnupiravir, have been approved for treating COVID-19 patients, but more are needed, because each drug has its limitation of usage and SARS-CoV-2 constantly develops drug resistance mutations. In addition, SARS-CoV-2 drugs have the potential to be repurposed to inhibit new human coronaviruses, thus help to prepare for future coronavirus outbreaks. We have screened a library of microbial metabolites to discover new SARS-CoV-2 inhibitors. To facilitate this screening effort, we generated a recombinant SARS-CoV-2 Delta variant carrying the nano luciferase as a reporter for measuring viral infection. Six compounds were found to inhibit SARS-CoV-2 at the half maximal inhibitory concentration (IC50) below 1 mM, including the anthracycline drug aclarubicin that markedly reduced viral RNA-dependent RNA polymerase (RdRp)-mediated gene expression, whereas other anthracyclines inhibited SARS-CoV-2 by activating the expression of interferon and antiviral genes. As the most commonly prescribed anti-cancer drugs, anthracyclines hold the promise of becoming new SARS-CoV-2 inhibitors.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Mitoxantrone, which did not activate ISG expression, inhibited SARS-CoV-2 to a higher fold when used to pretreat Calu-3 cells (Fig. 5F), which is likely because mitoxantrone targets the SARS-CoV-2 Spike-heparan sulfate complex and impairs virus entry (45).…”

Section: Resultsmentioning

confidence: 99%

Anthracyclines inhibit SARS-CoV-2 infection

Wang

Pan²,

Ma³

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Vimentin (Vim) is a type III intermediate filament-forming protein and an essential cytoskeleton element. In addition, Vim exists in the extracellular environment and on the surface of various cells regardless of its expression due to its secretion by immune cells triggered by inflammation [44] and by endothelial cells in tumours [39]. Recent studies have shown that Vim directly interacts with S-protein, and that blocking Vim on the cell surface significantly reduces the entry www.journals.viamedica.pl/neurologia_neurochirurgia_polska Figure 1.…”

Section: Extracellular Vimentinmentioning

confidence: 99%

“…Interestingly, the S-protein interacts with cellular HS through a domain adjacent to its receptor-binding domain (RBD) [43]. Furthermore, HS inhibitors, such as heparin derivatives and mitoxantrone, may directly block the interaction between HS and S1 protein, inhibiting the uptake of both pseudotyped and authentic SARS--CoV-2 [44]. Similar effects have been observed for sunitinib and BNTX, drugs that indirectly inhibit HS-mediated viral entry by rearrangement of the actin network [49].…”

Section: Heparan Sulfatementioning

confidence: 99%

Blood-brain barrier function in response to SARS-CoV-2 and its spike protein

Suprewicz

Fiedoruk

Czarnowska

et al. 2023

Neurol Neurochir Pol.

View full text Add to dashboard Cite

The typical manifestation of coronavirus 2 (CoV-2) infection is a severe acute respiratory syndrome (SARS) accompanied by pneumonia (COVID-19). However, SARS-CoV-2 can also affect the brain, causing chronic neurological symptoms, variously known as long, post, post-acute, or persistent COVID-19 condition, and affecting up to 40% of patients. The symptoms (fatigue, dizziness, headache, sleep disorders, malaise, disturbances of memory and mood) usually are mild and resolve spontaneously. However, some patients develop acute and fatal complications, including stroke or encephalopathy. Damage to the brain vessels mediated by the coronavirus spike protein (S-protein) and overactive immune responses have been identified as leading causes of this condition. However, the molecular mechanism by which the virus affects the brain still needs to be fully delineated. In this review article, we focus on interactions between host molecules and S-protein as the mechanism allowing the transit of SARS-CoV-2 through the blood-brain barrier to reach the brain structures. In addition, we discuss the impact of S-protein mutations and the involvement of other cellular factors conditioning the pathophysiology of SARS-CoV-2 infection. Finally, we review current and future COVID-19 treatment options.

show abstract

“…The fusion e ciency could be monitored by counting the number of nuclei per syncytium under uorescence microscopy. In this assay, syncytium formation strictly depends on the spike in effector cells and ACE2 in acceptor cells 35 . Additionally, both PIXN and MTAN inhibited syncytium formation in this assay (Figure S3B, C) 35 , suggesting that the assay recapitulates virusassociated syncytium formation.…”

Section: Hs Promotes Spike-induced Syncytium Formationmentioning

confidence: 99%

Heparan sulfate promotes ACE2 super-cluster assembly to enhance SARS-CoV-2-associated syncytium formation

Zhang

Tang

Stancanelli³

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

The mechanism of syncytium formation, caused by spike-induced cell-cell fusion in severe COVID-19, is largely unclear. Here we combine chemical genetics with 4D confocal imaging to establish the cell surface heparan sulfate (HS) as a critical host factor exploited by SARS-CoV-2 to enhance spike’s fusogenic activity. HS binds spike to facilitate ACE2 clustering, generating synapse-like cell-cell contacts to promote fusion pore formation. ACE2 clustering, and thus, syncytium formation is significantly mitigated by chemical or genetic elimination of cell surface HS, while in a cell-free system consisting of purified HS, spike, and lipid-anchored ACE2, HS directly induces ACE2 clustering. Importantly, the interaction of HS with spike allosterically enables a conserved ACE2 linker in receptor clustering, which concentrates spike at the fusion site to overcome fusion-associated activity loss. This fusion-boosting mechanism can be effectively targeted by an investigational HS-binding drug, which reduces syncytium formation in vitro and viral infection in mice.

show abstract

Mitoxantrone modulates a heparan sulfate-spike complex to inhibit SARS-CoV-2 infection

Cited by 11 publications

References 42 publications

Anthracyclines inhibit SARS-CoV-2 infection

Anthracyclines inhibit SARS-CoV-2 infection

Blood-brain barrier function in response to SARS-CoV-2 and its spike protein

Heparan sulfate promotes ACE2 super-cluster assembly to enhance SARS-CoV-2-associated syncytium formation

Contact Info

Product

Resources

About