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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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Main Authors: Alexandra Sakai (Author), Gagandeep Singh (Author), Mahsa Khoshbakht (Author), Scott Bittner (Author), Christiane V. Löhr (Author), Randy Diaz-Tapia (Author), Prajakta Warang (Author), Kris White (Author), Luke Le Luo (Author), Blanton Tolbert (Author), Mario Blanco (Author), Amy Chow (Author), Mitchell Guttman (Author), Cuiping Li (Author), Yiming Bao (Author), Joses Ho (Author), Sebastian Maurer-Stroh (Author), Arnab Chatterjee (Author), Sumit Chanda (Author), Adolfo García-Sastre (Author), Michael Schotsaert (Author), John R. Teijaro (Author), Hong M. Moulton (Author), David A. Stein (Author)
Format: Book
Published: Elsevier, 2024-12-01T00:00:00Z.
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Summary: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.
Item Description:2162-2531
10.1016/j.omtn.2024.102331

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