Inhibition of SARS-CoV-2 growth in the lungs of mice by a peptide-conjugated morpholino oligomer targeting viral RNA
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 genom...
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Elsevier,
2024-12-01T00:00:00Z.
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| 700 | 1 | 0 | |a Gagandeep Singh |e author |
| 700 | 1 | 0 | |a Mahsa Khoshbakht |e author |
| 700 | 1 | 0 | |a Scott Bittner |e author |
| 700 | 1 | 0 | |a Christiane V. Löhr |e author |
| 700 | 1 | 0 | |a Randy Diaz-Tapia |e author |
| 700 | 1 | 0 | |a Prajakta Warang |e author |
| 700 | 1 | 0 | |a Kris White |e author |
| 700 | 1 | 0 | |a Luke Le Luo |e author |
| 700 | 1 | 0 | |a Blanton Tolbert |e author |
| 700 | 1 | 0 | |a Mario Blanco |e author |
| 700 | 1 | 0 | |a Amy Chow |e author |
| 700 | 1 | 0 | |a Mitchell Guttman |e author |
| 700 | 1 | 0 | |a Cuiping Li |e author |
| 700 | 1 | 0 | |a Yiming Bao |e author |
| 700 | 1 | 0 | |a Joses Ho |e author |
| 700 | 1 | 0 | |a Sebastian Maurer-Stroh |e author |
| 700 | 1 | 0 | |a Arnab Chatterjee |e author |
| 700 | 1 | 0 | |a Sumit Chanda |e author |
| 700 | 1 | 0 | |a Adolfo García-Sastre |e author |
| 700 | 1 | 0 | |a Michael Schotsaert |e author |
| 700 | 1 | 0 | |a John R. Teijaro |e author |
| 700 | 1 | 0 | |a Hong M. Moulton |e author |
| 700 | 1 | 0 | |a David A. Stein |e author |
| 245 | 0 | 0 | |a Inhibition of SARS-CoV-2 growth in the lungs of mice by a peptide-conjugated morpholino oligomer targeting viral RNA |
| 260 | |b Elsevier, |c 2024-12-01T00:00:00Z. | ||
| 500 | |a 2162-2531 | ||
| 500 | |a 10.1016/j.omtn.2024.102331 | ||
| 520 | |a 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. | ||
| 546 | |a EN | ||
| 690 | |a MT: Oligonucleotides: Therapies and Applications | ||
| 690 | |a peptide-conjugated morpholino oligomer | ||
| 690 | |a PPMO | ||
| 690 | |a antisense | ||
| 690 | |a antiviral | ||
| 690 | |a SARS-CoV-2 | ||
| 690 | |a Therapeutics. Pharmacology | ||
| 690 | |a RM1-950 | ||
| 655 | 7 | |a article |2 local | |
| 786 | 0 | |n Molecular Therapy: Nucleic Acids, Vol 35, Iss 4, Pp 102331- (2024) | |
| 787 | 0 | |n http://www.sciencedirect.com/science/article/pii/S216225312400218X | |
| 787 | 0 | |n https://doaj.org/toc/2162-2531 | |
| 856 | 4 | 1 | |u https://doaj.org/article/cde8602c5de243599a35a2d086e74e3b |z Connect to this object online. |