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- Title
Inhibition of SARS-CoV-2 in Vero cell cultures by peptide-conjugated morpholino oligomers.
- Authors
Rosenke, Kyle; Leventhal, Shanna; Moulton, Hong M; Hatlevig, Susan; Hawman, David; Feldmann, Heinz; Stein, David A
- Abstract
<bold>Background: </bold>As the causative agent of COVID-19, SARS-CoV-2 is a pathogen of immense importance to global public health. Development of innovative direct-acting antiviral agents is sorely needed to address this virus. Peptide-conjugated morpholino oligomers (PPMO) are antisense compounds composed of a phosphorodiamidate morpholino oligomer covalently conjugated to a cell-penetrating peptide. PPMO require no delivery assistance to enter cells and are able to reduce expression of targeted RNA through sequence-specific steric blocking.<bold>Methods: </bold>Five PPMO designed against sequences of genomic RNA in the SARS-CoV-2 5'-untranslated region and a negative control PPMO of random sequence were synthesized. Each PPMO was evaluated for its effect on the viability of uninfected cells and its inhibitory effect on the replication of SARS-CoV-2 in Vero-E6 cell cultures. Cell viability was evaluated with an ATP-based method using a 48 h PPMO treatment time. Viral growth was measured with quantitative RT-PCR and TCID50 infectivity assays from experiments where cells received a 5 h PPMO treatment time.<bold>Results: </bold>PPMO designed to base-pair with sequence in the 5' terminal region or the leader transcription regulatory sequence region of SARS-CoV-2 genomic RNA were highly efficacious, reducing viral titres by up to 4-6 log10 in cell cultures at 48-72 h post-infection, in a non-toxic and dose-responsive manner.<bold>Conclusions: </bold>The data indicate that PPMO have the ability to potently and specifically suppress SARS-CoV-2 growth and are promising candidates for further preclinical development.
- Subjects
SARS-CoV-2; CELL culture; COVID-19; OLIGOMERS; ANTIVIRAL agents; NUCLEOTIDE sequence
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2021, Vol 76, Issue 2, p413
- ISSN
0305-7453
- Publication type
Journal Article
- DOI
10.1093/jac/dkaa460