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Molecular therapy. Nucleic acids
Dec 10, 2024;35 (4): 102331.

Inhibition of SARS-CoV-2 growth in the lungs of mice by a peptide-conjugated morpholino oligomer targeting viral RNA.

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
Author Information
  1. Alexandra Sakai: Scripps Research Institute, La Jolla, CA 92037, USA.
  2. Gagandeep Singh: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  3. Mahsa Khoshbakht: Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA.
  4. Scott Bittner: Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA.
  5. Christiane V Löhr: Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA.
  6. Randy Diaz-Tapia: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  7. Prajakta Warang: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  8. Kris White: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  9. Luke Le Luo: Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
  10. Blanton Tolbert: Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
  11. Mario Blanco: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
  12. Amy Chow: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
  13. Mitchell Guttman: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
  14. Cuiping Li: National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China.
  15. Yiming Bao: National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China.
  16. Joses Ho: GISAID @ A∗STAR Bioinformatics Institute, Singapore 138632, Singapore.
  17. Sebastian Maurer-Stroh: GISAID @ A∗STAR Bioinformatics Institute, Singapore 138632, Singapore.
  18. Arnab Chatterjee: Scripps Research Institute, La Jolla, CA 92037, USA.
  19. Sumit Chanda: Scripps Research Institute, La Jolla, CA 92037, USA.
  20. Adolfo García-Sastre: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  21. Michael Schotsaert: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  22. John R Teijaro: Scripps Research Institute, La Jolla, CA 92037, USA.
  23. Hong M Moulton: Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA.
  24. David A Stein: Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA.
PMID: 39376996 DOI: 10.1016/j.omtn.2024.102331

Abstract

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 and . In HeLa-ACE 2 cells, 5'END-2 produced IC values of between 40 nM and 1.15 μM in challenges using six genetically disparate strains of SARS-CoV-2, including JN.1. , 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.

Keywords

K-18-hACE2 mouse model MT: Oligonucleotides: Therapies and Applications PPMO RNA virus SARS-CoV-2 antisense antiviral intranasal delivery intratracheal delivery peptide-conjugated morpholino oligomer

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