Long-chain polyphosphates impair SARS-CoV-2 infection and replication
| Autor: | Sergio Brandi, Bianca Maria Pierri, Giorgia Borriello, Ettore Capoluongo, Barbara Izzo, Giuseppe Castaldo, Angelo Boccia, Hong-Yeoul Kim, Lorenzo Chiariotti, Giovanna Fusco, Rosa Della Monica, Dae-Young Kong, Ilaria Iacobucci, Maurizio Viscardi, Margherita Passariello, Roberto Siciliano, Stefano Pascarella, Claudia Tiberio, Camilla Anastasio, Giovanni Paolella, Fatemeh Asadzadeh, Jae-Ho Cheong, Pellegrino Cerino, Luigi Atripaldi, Marika Comegna, Martina Bianchi, Maria Chiara Monti, Fabrizio Quarantelli, Laura Marrone, Kyong-Seop Yun, Ida Pisano, Massimo Zollo, Giuseppina Criscuolo, Claudia De Lorenzo, Veronica Ferrucci |
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| Přispěvatelé: | 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. |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
viruses Virus Replication Biochemistry chemistry.chemical_compound Host Microbial Interaction 0302 clinical medicine HEK293 Cell Polyphosphates RNA polymerase Chlorocebus aethiops Proteolysi skin and connective tissue diseases Peptide sequence Protein Interaction Domains and Motif Research Articles Subgenomic mRNA Caco-2 Cell Coronavirus RNA-Dependent RNA Polymerase Chemistry Molecular Docking Simulation 030220 oncology & carcinogenesis Cytokines RNA Viral Angiotensin-Converting Enzyme 2 inorganic polyphosphate Human Signal Transduction Research Article Proteasome Endopeptidase Complex In Vitro Techniques Chlorocebus aethiop Antiviral Agents Models Biological Virus Microbiology 03 medical and health sciences Viral entry Virology Polyphosphate Administration Inhalation Animals Humans Protein Interaction Domains and Motifs Amino Acid Sequence Cytokine Molecular Biology Vero Cells Antiviral Agent Host Microbial Interactions Sequence Homology Amino Acid Animal In Vitro Technique SARS-CoV-2 Nebulizers and Vaporizers fungi RNA COVID-19 Cell Biology STKE Research Articles respiratory tract diseases COVID-19 Drug Treatment body regions Coronavirus 030104 developmental biology HEK293 Cells Viral replication Proteolysis Vero Cell Vero cell Sars-CoV-2 Caco-2 Cells Nebulizers and Vaporizer |
| Zdroj: | Science Signaling |
| ISSN: | 1937-9145 |
| Popis: | Long-chain polyphosphates inhibit SARS-CoV-2 infection by targeting a host receptor and a viral RNA polymerase. Polyphosphates versus SARS-CoV-2 Long-chain, inorganic polyphosphates (polyPs), which are found in many cells in the blood, have cytoprotective and antiviral activities, particularly against HIV-1 infection. Ferrucci et al. tested the effects of polyPs of various lengths on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. Molecular docking and binding analyses showed that polyPs bound to the host receptor ACE2, which facilitates viral entry, and a viral RNA polymerase required for replication. Both proteins underwent proteasomal degradation in cells incubated with polyP120, the optimal species tested, resulting in inhibition of SARS-CoV-2 replication and a reduced inflammatory response. Given that polyPs have low toxicity, these results suggest that their potential therapeutic use should be further explored. 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. |
| Databáze: | OpenAIRE |
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