A novel multitargeted self-assembling peptide-siRNA complex for simultaneous inhibition of SARS-CoV-2-host cell interaction and replication.

Autor:	Tuttolomondo M; Department of Molecular Medicine, Unit of Cancer and Inflammation Research, University of Southern Denmark, 5000 Odense, Denmark., Pham STD; Department of Molecular Medicine, Unit of Cancer and Inflammation Research, University of Southern Denmark, 5000 Odense, Denmark., Terp MG; Department of Molecular Medicine, Unit of Cancer and Inflammation Research, University of Southern Denmark, 5000 Odense, Denmark., Cendán Castillo V; Department of Molecular Medicine, Unit of Cancer and Inflammation Research, University of Southern Denmark, 5000 Odense, Denmark., Kalisi N; Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, 5000 Odense, Denmark., Vogel S; Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, 5000 Odense, Denmark., Langkjær N; Department of Nuclear Medicine, Odense University Hospital, 5000 Odense, Denmark.; Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark., Hansen UM; Department of Molecular Medicine, Imaging Core Facility, DaMBIC, University of Southern Denmark, 5000 Odense, Denmark., Thisgaard H; Department of Nuclear Medicine, Odense University Hospital, 5000 Odense, Denmark.; Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark., Schrøder HD; Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark.; Department of Pathology, Odense University Hospital, 5000 Odense, Denmark., Palarasah Y; Department of Molecular Medicine, Unit of Cancer and Inflammation Research, University of Southern Denmark, 5000 Odense, Denmark., Ditzel HJ; Department of Molecular Medicine, Unit of Cancer and Inflammation Research, University of Southern Denmark, 5000 Odense, Denmark.; Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark.; Department of Oncology, Odense University Hospital, 5000 Odense, Denmark.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2024 May 24; Vol. 35 (3), pp. 102227. Date of Electronic Publication: 2024 May 24 (Print Publication: 2024).
DOI:	10.1016/j.omtn.2024.102227
Abstrakt:	Effective therapeutics are necessary for managing severe COVID-19 disease despite the availability of vaccines. Small interfering RNA (siRNA) can silence viral genes and restrict SARS-CoV-2 replication. Cell-penetrating peptides is a robust method for siRNA delivery, enhancing siRNA stability and targeting specific receptors. We developed a peptide HE25 that blocks SARS-CoV-2 replication by various mechanisms, including the binding of multiple receptors involved in the virus's internalization, such as ACE2, integrins and NRP1. HE25 not only acts as a vehicle to deliver the SARS-CoV-2 RNA-dependent RNA polymerase siRNA into cells but also facilitates their internalization through endocytosis. Once inside endosomes, the siRNA is released into the cytoplasm through the Histidine-proton sponge effect and the selective cleavage of HE25 by cathepsin B. These mechanisms effectively inhibited the replication of the ancestral SARS-CoV-2 and the Omicron variant BA.5 in vitro . When HE25 was administered in vivo , either by intravenous injection or inhalation, it accumulated in lungs, veins and arteries, endothelium, or bronchial structure depending on the route. Furthermore, the siRNA/HE25 complex caused gene silencing in lung cells in vitro . The SARS-CoV-2 siRNA/HE25 complex is a promising therapeutic for COVID-19, and a similar strategy can be employed to combat future emerging viral diseases. Competing Interests: The authors declare no competing interests. (© 2024 The Author(s).)
Databáze:	MEDLINE
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