Title | Inhibition of SARS-CoV-2 in Vero cell cultures by peptide-conjugated morpholino oligomers. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Rosenke, K, Leventhal, S, Moulton, HM, Hatlevig, S, Hawman, D, Feldmann, H, Stein, DA |
Journal | J Antimicrob Chemother |
Volume | 76 |
Issue | 2 |
Pagination | 413-417 |
Date Published | 2021 01 19 |
ISSN | 1460-2091 |
Keywords | Animals, Antiviral Agents, Cell Survival, Cell-Penetrating Peptides, Chlorocebus aethiops, COVID-19, Cytopathogenic Effect, Viral, Morpholinos, SARS-CoV-2, Vero Cells, Virus Replication |
Abstract | BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. |
DOI | 10.1093/jac/dkaa460 |
Alternate Journal | J Antimicrob Chemother |
PubMed ID | 33164048 |
PubMed Central ID | PMC7717290 |