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

Authors
 Veronica Ferrucci  ;  Dae-Young Kong  ;  Fatemeh Asadzadeh  ;  Laura Marrone  ;  Angelo Boccia  ;  Roberto Siciliano  ;  Giuseppina Criscuolo  ;  Camilla Anastasio  ;  Fabrizio Quarantelli  ;  Marika Comegna  ;  Ida Pisano  ;  Margherita Passariello  ;  Ilaria Iacobucci  ;  Rosa Della Monica  ;  Barbara Izzo  ;  Pellegrino Cerino  ;  Giovanna Fusco  ;  Maurizio Viscardi  ;  Sergio Brandi  ;  Bianca Maria Pierri  ;  Giorgia Borriello  ;  Claudia Tiberio  ;  Luigi Atripaldi  ;  Martina Bianchi  ;  Giovanni Paolella  ;  Ettore Capoluongo  ;  Giuseppe Castaldo  ;  Lorenzo Chiariotti  ;  Maria Monti  ;  Claudia De Lorenzo  ;  Kyong-Seop Yun  ;  Stefano Pascarella  ;  Jae-Ho Cheong  ;  Hong-Yeoul Kim  ;  Massimo Zollo 
Citation
 SCIENCE SIGNALING, Vol.14(690) : eabe5040, 2021-07 
Journal Title
SCIENCE SIGNALING
ISSN
 1937-9145 
Issue Date
2021-07
MeSH
Administration, Inhalation ; Amino Acid Sequence ; Angiotensin-Converting Enzyme 2 / chemistry ; Angiotensin-Converting Enzyme 2 / metabolism ; Animals ; Antiviral Agents / administration & dosage ; Antiviral Agents / chemistry ; Antiviral Agents / pharmacology* ; COVID-19 / drug therapy* ; COVID-19 / metabolism ; COVID-19 / virology ; Caco-2 Cells ; Chlorocebus aethiops ; Coronavirus RNA-Dependent RNA Polymerase / chemistry ; Coronavirus RNA-Dependent RNA Polymerase / genetics ; Coronavirus RNA-Dependent RNA Polymerase / metabolism ; Cytokines / metabolism ; HEK293 Cells ; Host Microbial Interactions / drug effects ; Host Microbial Interactions / genetics ; Host Microbial Interactions / physiology ; Humans ; In Vitro Techniques ; Models, Biological ; Molecular Docking Simulation ; Nebulizers and Vaporizers ; Polyphosphates / administration & dosage ; Polyphosphates / chemistry ; Polyphosphates / pharmacology* ; Proteasome Endopeptidase Complex / metabolism ; Protein Interaction Domains and Motifs ; Proteolysis / drug effects ; RNA, Viral / genetics ; RNA, Viral / metabolism ; SARS-CoV-2 / drug effects* ; SARS-CoV-2 / genetics ; SARS-CoV-2 / physiology ; Sequence Homology, Amino Acid ; Signal Transduction / drug effects ; Vero Cells ; Virus Replication / drug effects
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.
Files in This Item:
T202105474.pdf Download
DOI
10.1126/scisignal.abe5040
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Cheong, Jae Ho(정재호) ORCID logo https://orcid.org/0000-0002-1703-1781
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/187309
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