Silencing of SARS-CoV-2 with modified siRNA-peptide dendrimer formulation.
| Title: | Silencing of SARS-CoV-2 with modified siRNA-peptide dendrimer formulation. |
|---|---|
| Authors: | Khaitov M; NRC Institute of Immunology FMBA, Moscow, Russia.; Nikonova A; NRC Institute of Immunology FMBA, Moscow, Russia.; Mechnikov Research Institute for Vaccines and Sera, Moscow, Russia.; Shilovskiy I; NRC Institute of Immunology FMBA, Moscow, Russia.; Kozhikhova K; NRC Institute of Immunology FMBA, Moscow, Russia.; Kofiadi I; NRC Institute of Immunology FMBA, Moscow, Russia.; Vishnyakova L; NRC Institute of Immunology FMBA, Moscow, Russia.; Nikolskii A; NRC Institute of Immunology FMBA, Moscow, Russia.; Gattinger P; Medical University of Vienna, Vienna, Austria.; Kovchina V; NRC Institute of Immunology FMBA, Moscow, Russia.; Barvinskaia E; NRC Institute of Immunology FMBA, Moscow, Russia.; Yumashev K; NRC Institute of Immunology FMBA, Moscow, Russia.; Smirnov V; NRC Institute of Immunology FMBA, Moscow, Russia.; Maerle A; NRC Institute of Immunology FMBA, Moscow, Russia.; Kozlov I; NRC Institute of Immunology FMBA, Moscow, Russia.; Shatilov A; NRC Institute of Immunology FMBA, Moscow, Russia.; Timofeeva A; NRC Institute of Immunology FMBA, Moscow, Russia.; Andreev S; NRC Institute of Immunology FMBA, Moscow, Russia.; Koloskova O; NRC Institute of Immunology FMBA, Moscow, Russia.; Kuznetsova N; Federal State Budget Institution 'National Research Centre for Epidemiology and Microbiology named after Honorary Academician N. F.Gamaleya' of the Ministry of Health of the Russian Federation, Moscow, Russia.; Vasina D; Federal State Budget Institution 'National Research Centre for Epidemiology and Microbiology named after Honorary Academician N. F.Gamaleya' of the Ministry of Health of the Russian Federation, Moscow, Russia.; Nikiforova M; Federal State Budget Institution 'National Research Centre for Epidemiology and Microbiology named after Honorary Academician N. F.Gamaleya' of the Ministry of Health of the Russian Federation, Moscow, Russia.; Rybalkin S; NRC Institute of Immunology FMBA, Moscow, Russia.; Sergeev I; NRC Institute of Immunology FMBA, Moscow, Russia.; Trofimov D; NRC Institute of Immunology FMBA, Moscow, Russia.; Martynov A; NRC Institute of Immunology FMBA, Moscow, Russia.; Berzin I; Federal Medico-biological Agency of Russia (FMBA Russia), Moscow, Russia.; Gushchin V; Federal State Budget Institution 'National Research Centre for Epidemiology and Microbiology named after Honorary Academician N. F.Gamaleya' of the Ministry of Health of the Russian Federation, Moscow, Russia.; Kovalchuk A; 48 Central Research Institute of the Ministry of Defense of the Russian Federation, Moscow, Russia.; Borisevich S; 48 Central Research Institute of the Ministry of Defense of the Russian Federation, Moscow, Russia.; Valenta R; NRC Institute of Immunology FMBA, Moscow, Russia.; Medical University of Vienna, Vienna, Austria.; Khaitov R; NRC Institute of Immunology FMBA, Moscow, Russia.; Skvortsova V; Federal Medico-biological Agency of Russia (FMBA Russia), Moscow, Russia. |
| Source: | Allergy [Allergy] 2021 Sep; Vol. 76 (9), pp. 2840-2854. Date of Electronic Publication: 2021 May 10. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Wiley-Blackwell Country of Publication: Denmark NLM ID: 7804028 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1398-9995 (Electronic) Linking ISSN: 01054538 NLM ISO Abbreviation: Allergy Subsets: MEDLINE |
| Imprint Name(s): | Publication: Copenhagen : Wiley-Blackwell; Original Publication: Copenhagen, Munksgaard. |
| MeSH Terms: | COVID-19* ; Dendrimers*; Peptides/genetics ; RNA, Small Interfering/genetics ; Animals ; Antiviral Agents ; Humans ; RNA, Viral ; SARS-CoV-2 |
| Abstract: | Background: First vaccines for prevention of Coronavirus disease 2019 (COVID-19) are becoming available but there is a huge and unmet need for specific forms of treatment. In this study we aimed to evaluate the anti-SARS-CoV-2 effect of siRNA both in vitro and in vivo.; Methods: To identify the most effective molecule out of a panel of 15 in silico designed siRNAs, an in vitro screening system based on vectors expressing SARS-CoV-2 genes fused with the firefly luciferase reporter gene and SARS-CoV-2-infected cells was used. The most potent siRNA, siR-7, was modified by Locked nucleic acids (LNAs) to obtain siR-7-EM with increased stability and was formulated with the peptide dendrimer KK-46 for enhancing cellular uptake to allow topical application by inhalation of the final formulation - siR-7-EM/KK-46. Using the Syrian Hamster model for SARS-CoV-2 infection the antiviral capacity of siR-7-EM/KK-46 complex was evaluated.; Results: We identified the siRNA, siR-7, targeting SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) as the most efficient siRNA inhibiting viral replication in vitro. Moreover, we showed that LNA-modification and complexation with the designed peptide dendrimer enhanced the antiviral capacity of siR-7 in vitro. We demonstrated significant reduction of virus titer and lung inflammation in animals exposed to inhalation of siR-7-EM/KK-46 in vivo.; Conclusions: Thus, we developed a therapeutic strategy for COVID-19 based on inhalation of a modified siRNA-peptide dendrimer formulation. The developed medication is intended for inhalation treatment of COVID-19 patients.; (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.) |
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| Grant Information: | Federal Medico-biological Agency of Russia |
| Contributed Indexing: | Keywords: COVID-19; LNA; SARS-CoV-2; peptide dendrimers; siRNA |
| Substance Nomenclature: | 0 (Antiviral Agents); 0 (Dendrimers); 0 (Peptides); 0 (RNA, Small Interfering); 0 (RNA, Viral) |
| Entry Date(s): | Date Created: 20210410 Date Completed: 20210903 Latest Revision: 20221005 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC8251148 |
| DOI: | 10.1111/all.14850 |
| PMID: | 33837568 |
| Database: | MEDLINE |
Journal Article