tetano
Editor, Senior Moderator
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[SUP] 1 2 [/SUP], Dae-Young Kong[SUP] 3 [/SUP], Fatemeh Asadzadeh[SUP] 1 [/SUP], Laura Marrone[SUP] 1 2 [/SUP], Angelo Boccia[SUP] 2 [/SUP], Roberto Siciliano[SUP] 1 [/SUP], Giuseppina Criscuolo[SUP] 1 2 [/SUP], Camilla Anastasio[SUP] 1 [/SUP], Fabrizio Quarantelli[SUP] 1 [/SUP], Marika Comegna[SUP] 1 2 [/SUP], Ida Pisano[SUP] 1 [/SUP], Margherita Passariello[SUP] 1 2 [/SUP], Ilaria Iacobucci[SUP] 1 4 [/SUP], Rosa Della Monica[SUP] 1 [/SUP], Barbara Izzo[SUP] 1 2 [/SUP], Pellegrino Cerino[SUP] 5 [/SUP], Giovanna Fusco[SUP] 5 [/SUP], Maurizio Viscardi[SUP] 5 [/SUP], Sergio Brandi[SUP] 5 [/SUP], Bianca Maria Pierri[SUP] 5 [/SUP], Giorgia Borriello[SUP] 5 [/SUP], Claudia Tiberio[SUP] 6 [/SUP], Luigi Atripaldi[SUP] 6 [/SUP], Martina Bianchi[SUP] 7 [/SUP], Giovanni Paolella[SUP] 1 2 [/SUP], Ettore Capoluongo[SUP] 1 8 [/SUP], Giuseppe Castaldo[SUP] 1 2 [/SUP], Lorenzo Chiariotti[SUP] 1 2 [/SUP], Maria Monti[SUP] 1 4 [/SUP], Claudia De Lorenzo[SUP] 1 2 [/SUP], Kyong-Seop Yun[SUP] 9 [/SUP], Stefano Pascarella[SUP] 7 [/SUP], Jae-Ho Cheong[SUP] 10 [/SUP], Hong-Yeoul Kim[SUP] 11 9 [/SUP], Massimo Zollo[SUP] 12 2 8 [/SUP]
Affiliations
Abstract
Inorganic polyphosphates (polyPs) are linear polymers composed of repeated phosphate (PO[SUB]4[/SUB] [SUP]3-[/SUP]) 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.
. 2021 Jul 6;14(690):eabe5040.
doi: 10.1126/scisignal.abe5040.
Long-chain polyphosphates impair SARS-CoV-2 infection and replication
Veronica Ferrucci[SUP] 1 2 [/SUP], Dae-Young Kong[SUP] 3 [/SUP], Fatemeh Asadzadeh[SUP] 1 [/SUP], Laura Marrone[SUP] 1 2 [/SUP], Angelo Boccia[SUP] 2 [/SUP], Roberto Siciliano[SUP] 1 [/SUP], Giuseppina Criscuolo[SUP] 1 2 [/SUP], Camilla Anastasio[SUP] 1 [/SUP], Fabrizio Quarantelli[SUP] 1 [/SUP], Marika Comegna[SUP] 1 2 [/SUP], Ida Pisano[SUP] 1 [/SUP], Margherita Passariello[SUP] 1 2 [/SUP], Ilaria Iacobucci[SUP] 1 4 [/SUP], Rosa Della Monica[SUP] 1 [/SUP], Barbara Izzo[SUP] 1 2 [/SUP], Pellegrino Cerino[SUP] 5 [/SUP], Giovanna Fusco[SUP] 5 [/SUP], Maurizio Viscardi[SUP] 5 [/SUP], Sergio Brandi[SUP] 5 [/SUP], Bianca Maria Pierri[SUP] 5 [/SUP], Giorgia Borriello[SUP] 5 [/SUP], Claudia Tiberio[SUP] 6 [/SUP], Luigi Atripaldi[SUP] 6 [/SUP], Martina Bianchi[SUP] 7 [/SUP], Giovanni Paolella[SUP] 1 2 [/SUP], Ettore Capoluongo[SUP] 1 8 [/SUP], Giuseppe Castaldo[SUP] 1 2 [/SUP], Lorenzo Chiariotti[SUP] 1 2 [/SUP], Maria Monti[SUP] 1 4 [/SUP], Claudia De Lorenzo[SUP] 1 2 [/SUP], Kyong-Seop Yun[SUP] 9 [/SUP], Stefano Pascarella[SUP] 7 [/SUP], Jae-Ho Cheong[SUP] 10 [/SUP], Hong-Yeoul Kim[SUP] 11 9 [/SUP], Massimo Zollo[SUP] 12 2 8 [/SUP]
Affiliations
- PMID: 34230209
- DOI: 10.1126/scisignal.abe5040
Abstract
Inorganic polyphosphates (polyPs) are linear polymers composed of repeated phosphate (PO[SUB]4[/SUB] [SUP]3-[/SUP]) 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.