| Autor: |
Alexandra Sakai, Gagandeep Singh, Mahsa Khoshbakht, Scott Bittner, Christiane V. Löhr, Randy Diaz-Tapia, Prajakta Warang, Kris White, Luke Le Luo, Blanton Tolbert, Mario Blanco, Amy Chow, Mitchell Guttman, Cuiping Li, Yiming Bao, Joses Ho, Sebastian Maurer-Stroh, Arnab Chatterjee, Sumit Chanda, Adolfo García-Sastre, Michael Schotsaert, John R. Teijaro, Hong M. Moulton, David A. Stein |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
Molecular Therapy: Nucleic Acids, Vol 35, Iss 4, Pp 102331- (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2162-2531 |
| DOI: |
10.1016/j.omtn.2024.102331 |
| Popis: |
Further development of direct-acting antiviral agents against human SARS-CoV-2 infections remains a public health priority. Here, we report that an antisense peptide-conjugated morpholino oligomer (PPMO) named 5′END-2, targeting a highly conserved sequence in the 5′ UTR of SARS-CoV-2 genomic RNA, potently suppressed SARS-CoV-2 growth in vitro and in vivo. In HeLa-ACE 2 cells, 5′END-2 produced IC50 values of between 40 nM and 1.15 μM in challenges using six genetically disparate strains of SARS-CoV-2, including JN.1. In vivo, using K18-hACE2 mice and the WA-1/2020 virus isolate, two doses of 5′END-2 at 10 mg/kg, administered intranasally on the day before and the day after infection, produced approximately 1.4 log10 virus titer reduction in lung tissue at 3 days post-infection. Under a similar dosing schedule, intratracheal administration of 1.0–2.0 mg/kg 5′END-2 produced over 3.5 log10 virus growth suppression in mouse lungs. Electrophoretic mobility shift assays characterized specific binding of 5′END-2 to its complementary target RNA. Furthermore, using reporter constructs containing SARS-CoV-2 5′ UTR leader sequence, in an in-cell system, we observed that 5′END-2 could interfere with translation in a sequence-specific manner. The results demonstrate that direct pulmonary delivery of 5′END-2 PPMO is a promising antiviral strategy against SARS-CoV-2 infections and warrants further development. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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