Antiviral activity of long-chain polyphosphates against SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense and single-stranded RNA virus that has caused the current ongoing coronavirus disease 2019 (COVID-19) pandemic. After entering the host cells, SARS-CoV-2 starts replicating its genomic RNA to produce smaller RNAs or subgenomic RNAs (sgRNAs). This virus replicates primarily in the lower respiratory tract.

How does SARS-CoV-2 infect a host cell?

The sgRNAs are involved with the production of conserved structural proteins, namely, spike (S), envelope (E), membrane (M), and nucleocapsid (N). The S protein binds to the angiotensin-converting enzyme 2 (ACE2) receptor present on the host’s cell surface. Two receptors associated with virus-host interactions are ACE2 and cellular serine protease transmembrane serine protease 2 (TMPRSS2). The chances of the virus binding to ACE2 are increased by heparan sulfate present on the cell surface. It modifies the structure of the viral S protein to assist the open conformation of the receptor-binding domain (RBD). Both structural and non-structural proteins aids in virus replication. Mutations have led to the emergence of SARS-CoV-2 variants, such as B.1.1.7, B1.351, and P1, that are more efficient in viral replication, transmission, and evasion of host immune responses. Hence, there is an urgent need to develop new therapeutic strategies that would effectively against these variants.

Long-chain inorganic polyphosphates (polyPs) and SARS-CoV-2 infection

PolyPs comprise chains of several hundreds of inorganic phosphate (Pi) units. These are abundantly present in peripheral blood mononuclear cells and erythrocytes. PolyPs are also found in the plasma membrane, nucleus, cytoplasm, and mitochondria. Some of the characteristic features of polyPs are blood coagulation, inhibition of the complement pathway, chelation of calcium (Ca2+) for bone mineralization, and promotion of apoptosis. Further, in vitro studies have revealed that linear polyPs possess cytoprotective and antiviral properties against HIV-1 infection. Most importantly, an in vitro study has shown that they can inhibit the interaction between RBD of SARS-CoV-2 S protein and ACE2.

A new study has been published in Science Signaling that has examined the potential role that long-chain inorganic polyphosphates (polyPs) play against SARS-CoV-2 infection.

The authors of the study have shown antiviral activities of long-chain inorganic polyPs against SARS-CoV-2 in various cellular models such as Vero E6, Caco2 cells, and primary human epithelial cells obtained from a healthy donor. They reported that intracellularly, polyPs increase the proteasome-mediated lowering in the abundance of ACE2 and RdRp through steric interruption. This leads to notable reductions in the amounts of SARS-CoV-2 structural sgRNAs and structural proteins. Further, as previous study has revealed that polyPs are non-toxic, the authors of the current study propose that therapeutic use of polyPs should be explored.

The mechanism by which long-chain polyPs inhibit the replication of SARS-CoV-2

The long-chain polyPs can inhibit the expression of SARS-CoV-2 viral genes. The initial mechanism of action involves long-chain polyPs that target ACE2 by increasing proteasome-mediated degradation of ACE2. Subsequently, the replication of the virus in host cells is impaired. The binding of polyPs to ACE2 is mediated by four amino acid residues of ACE2, which are reported to be conserved across different strains. This observation has been further substantiated with experiments that revealed polyP120 inhibits replication of the UK’s B1.1.7 variant. Such observation further aids in the application of polyPs for therapeutic purposes against COVID-19 disease. This study has further reported that upon treatment with polyPs, SARS-CoV-2–infected cells showed a reduction in ACE2 mRNA abundance. The second mechanism of action involves inhibition of RdRp. The polyPs bind to the SARS-CoV-2 RdRp protein and activate proteasome-mediated degradation. This binding is associated with five amino acid residues within the RdRp RNA binding site. In this mechanism, the long-chain polyPs decrease the expression of the main SARS-CoV-2 genes. This suggests that polyPs reduce active viral replication.

The authors of the present study have revealed throughout the model of action that polyP120 lowers the abundance of ACE2 and RdRp through proteasome-mediated degradation, and this antiviral activity is independent of any mutations in the RBD S variants. Further, researchers suggest the treatment of COVID-19 patients infected with the variant strains with polyP120 in an aerosol formulation.

Silico analyses using RASMOT 3D-PRO, HMMScan, DALI, PSI-Blast, and FATCAT, identified three-dimensional (3D) motifs of four specific residues in the ACE2 protein, among which, three are recognized as conserved motifs. Additionally, enhancement in the concentration of polyp leads to antiproliferative effects on primary human epithelial cells. The present research has also shown that polyP120 lessens the abundances of mRNAs that encode the main cytokines, i.e., IFN-g, IL-6, IL-10, and IL-12. These cytokines are associated with the cytokine storm that is sometimes found in the COVID-19 patients.

Key contribution of this research

The authors of the current study assume that if polyP120 lacks toxicity, given its function, it can be used to treat patients infected with SARS-CoV-2. This can be used alone or in combination, e.g., along with inhibitors of RdRp-mediated RNA replication and transcription. Hence, antiviral functions of polyPs could be effectively exploited for preventing infections and progression of COVID-19 disease.

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