Inorganic polyphosphates (polyPs) are linear polymers composed of repeated phosphate (PO43−) 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.

Long-chain polyphosphates impair SARS-CoV-2 infection and replication / Ferrucci, V.; Kong, D. -Y.; Asadzadeh, F.; Marrone, L.; Boccia, A.; Siciliano, R.; Criscuolo, G.; Anastasio, C.; Quarantelli, F.; Comegna, M.; Pisano, I.; Passariello, M.; Iacobucci, I.; della Monica, R.; Izzo, B.; Cerino, P.; Fusco, G.; Viscardi, M.; Brandi, S.; Pierri, B. M.; Borriello, G.; Tiberio, C.; Atripaldi, L.; Bianchi, M.; Paolella, G.; Capoluongo, E.; Castaldo, G.; Chiariotti, L.; Monti, M.; de Lorenzo, C.; Yun, K. -S.; Pascarella, S.; Cheong, J. -H.; Kim, H. -Y.; Zollo, M.. - In: SCIENCE SIGNALING. - ISSN 1937-9145. - 14:690(2021), pp. 1-19. [10.1126/scisignal.abe5040]

Long-chain polyphosphates impair SARS-CoV-2 infection and replication

Ferrucci V.;Asadzadeh F.;Marrone L.;Siciliano R.;Comegna M.;Pisano I.;Passariello M.;Iacobucci I.;Izzo B.;Cerino P.;Brandi S.;Paolella G.;Capoluongo E.;Castaldo G.;Chiariotti L.;Monti M.;de Lorenzo C.;Pascarella S.;Zollo M.
2021

Abstract

Inorganic polyphosphates (polyPs) are linear polymers composed of repeated phosphate (PO43−) 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
Long-chain polyphosphates impair SARS-CoV-2 infection and replication / Ferrucci, V.; Kong, D. -Y.; Asadzadeh, F.; Marrone, L.; Boccia, A.; Siciliano, R.; Criscuolo, G.; Anastasio, C.; Quarantelli, F.; Comegna, M.; Pisano, I.; Passariello, M.; Iacobucci, I.; della Monica, R.; Izzo, B.; Cerino, P.; Fusco, G.; Viscardi, M.; Brandi, S.; Pierri, B. M.; Borriello, G.; Tiberio, C.; Atripaldi, L.; Bianchi, M.; Paolella, G.; Capoluongo, E.; Castaldo, G.; Chiariotti, L.; Monti, M.; de Lorenzo, C.; Yun, K. -S.; Pascarella, S.; Cheong, J. -H.; Kim, H. -Y.; Zollo, M.. - In: SCIENCE SIGNALING. - ISSN 1937-9145. - 14:690(2021), pp. 1-19. [10.1126/scisignal.abe5040]
File in questo prodotto:
File Dimensione Formato  
COVID_scisignal_2021.pdf

accesso aperto

Licenza: Dominio pubblico
Dimensione 1.3 MB
Formato Adobe PDF
1.3 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/870090
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 24
  • ???jsp.display-item.citation.isi??? 23
social impact