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 genomic RNA, potently suppressed SARS-CoV-2 growth <i>in vitro</i> and <i>in vivo</i>. In HeLa-ACE 2 cells, 5'END-2 produced IC<sub>50</sub> values of between 40 nM and 1.15 μM in challenges using six genetically disparate strains of SARS-CoV-2, including JN.1. <i>In vivo</i>, 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.
Authors
- Adolfo Garcı́a-Sastre (ORCID: https://orcid.org/0000-0002-6551-1827)
- Michael Schotsaert (ORCID: https://orcid.org/0000-0003-3156-3132)
- Sebastian Maurer‐Stroh (ORCID: https://orcid.org/0000-0003-0813-9640)
- Prajakta Warang (ORCID: https://orcid.org/0000-0002-5571-8277)
- Kris M. White (ORCID: https://orcid.org/0000-0003-0889-0506)
- Arnab K. Chatterjee (ORCID: https://orcid.org/0000-0001-5171-7982)
- David A. Stein (ORCID: https://orcid.org/0000-0002-5446-5167)
- Mario R. Blanco (ORCID: https://orcid.org/0000-0003-4503-0118)
- Mitchell Guttman (ORCID: https://orcid.org/0000-0003-4748-9352)
- Randy Diaz-Tapia
- Joses Ho (ORCID: https://orcid.org/0000-0002-9186-6322)
- Yīmíng Bào (ORCID: https://orcid.org/0000-0002-9922-9723)
- Sumit K. Chanda (ORCID: https://orcid.org/0000-0001-9399-7927)
- Christiane V. Löhr (ORCID: https://orcid.org/0000-0003-3787-5583)
- Scott Bittner
- Hong M. Moulton (ORCID: https://orcid.org/0000-0002-8095-1513)
- Gagandeep Singh (ORCID: https://orcid.org/0000-0002-7938-9391)
- John R. Teijaro (ORCID: https://orcid.org/0000-0001-8280-8887)
- Blanton S. Tolbert (ORCID: https://orcid.org/0000-0003-2456-0443)
- Cuiping Li (ORCID: https://orcid.org/0000-0002-9483-6452)
- Amy Chow
- Mahsa Khoshbakht
- Luke Le Luo
- A Sakai
Institutions
- California Institute of Technology (US)
- Scripps Research Institute (US)
- Oregon State University (US)
- Bioinformatics Institute (SG)
- University of Chinese Academy of Sciences (CN)
- Case Western Reserve University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Molecular Therapy — Nucleic Acids
- Published
- 2024-09-10
- DOI
- https://doi.org/10.1016/j.omtn.2024.102331
- Citations
- 4
- Primary Topic
- Respiratory viral infections research
- Type
- article
- Field-Weighted Citation Impact
- 1.55
Funders
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases