Sci Signal . Long-chain polyphosphates impair SARS-CoV-2 infection and replication

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Sci Signal


. 2021 Jul 6;14(690):eabe5040.
doi: 10.1126/scisignal.abe5040.
Long-chain polyphosphates impair SARS-CoV-2 infection and replication


Veronica Ferrucci ^{1 2} , Dae-Young Kong ³ , Fatemeh Asadzadeh ¹ , Laura Marrone ^{1 2} , Angelo Boccia ² , Roberto Siciliano ¹ , Giuseppina Criscuolo ^{1 2} , Camilla Anastasio ¹ , Fabrizio Quarantelli ¹ , Marika Comegna ^{1 2} , Ida Pisano ¹ , Margherita Passariello ^{1 2} , Ilaria Iacobucci ^{1 4} , Rosa Della Monica ¹ , Barbara Izzo ^{1 2} , Pellegrino Cerino ⁵ , Giovanna Fusco ⁵ , Maurizio Viscardi ⁵ , Sergio Brandi ⁵ , Bianca Maria Pierri ⁵ , Giorgia Borriello ⁵ , Claudia Tiberio ⁶ , Luigi Atripaldi ⁶ , Martina Bianchi ⁷ , Giovanni Paolella ^{1 2} , Ettore Capoluongo ^{1 8} , Giuseppe Castaldo ^{1 2} , Lorenzo Chiariotti ^{1 2} , Maria Monti ^{1 4} , Claudia De Lorenzo ^{1 2} , Kyong-Seop Yun ⁹ , Stefano Pascarella ⁷ , Jae-Ho Cheong ¹⁰ , Hong-Yeoul Kim ^{11 9} , Massimo Zollo ^{12 2 8}



Affiliations

• PMID: 34230209
• DOI: 10.1126/scisignal.abe5040

Abstract

Inorganic polyphosphates (polyPs) are linear polymers composed of repeated phosphate (PO₄ ^3-) units linked together by multiple high-energy phosphoanhydride bonds. In addition to being a source of energy, polyPs have cytoprotective and antiviral activities. Here, we investigated the antiviral activities of long-chain polyPs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In molecular docking analyses, polyPs interacted with several conserved amino acid residues in angiotensin-converting enzyme 2 (ACE2), the host receptor that facilitates virus entry, and in viral RNA-dependent RNA polymerase (RdRp). ELISA and limited proteolysis assays using nano- LC-MS/MS mapped polyP120 binding to ACE2, and site-directed mutagenesis confirmed interactions between ACE2 and SARS-CoV-2 RdRp and identified the specific amino acid residues involved. PolyP120 enhanced the proteasomal degradation of both ACE2 and RdRp, thus impairing replication of the British B.1.1.7 SARS-CoV-2 variant. We thus tested polyPs for functional interactions with the virus in SARS-CoV-2-infected Vero E6 and Caco2 cells and in primary human nasal epithelial cells. Delivery of a nebulized form of polyP120 reduced the amounts of viral positive-sense genomic and subgenomic RNAs, of RNA transcripts encoding proinflammatory cytokines, and of viral structural proteins, thereby presenting SARS-CoV-2 infection in cells in vitro.