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.
Highlights
Coronaviruses (CoVs) contain positive-sense, single-stranded RNA (~30 kb)
PolyPs enhanced the proteasome-mediated decrease in the abundance of angiotensin-converting enzyme 2 (ACE2) and RNA-dependent RNA polymerase (RdRp) through steric hindrance, which resulted in marked reductions in the amounts of SARS-CoV-2 structural sgRNAs and proteins
CoV-2 viral particles obtained from a Korean patient who was positive for COVID-19
Summary
Four major categories have been reported, with alpha-CoVs and beta-CoVs known to infect humans These viruses replicate in the lower respiratory tract and cause pneumonia, which can be fatal [1, 2]. These infections include severe acute respiratory syndrome (SARS-CoV), Middle East respiratory syndrome (MERS-CoV), and SARS-CoV-2. This last CoV belongs to the beta CoV genus [3] and has resulted in pandemic acute respiratory syndrome in humans, known as coronavirus disease 2019 (COVID-19). As for the other respiratory CoVs, SARS-CoV-2 is transmitted by respiratory droplets, with fecal-oral transmission possible [5]
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