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Silencing of SARS-CoV-2 with modified siRNA-peptide dendrimer formulation
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  • Musa Khaitov,
  • Alexandra Nikonova,
  • Igor Shilovskiy ,
  • Ksenia Kozhikhova ,
  • Ilya Kofiadi ,
  • Lyudmila Vishnyakova ,
  • Aleksandr Nikolskii ,
  • Pia Gattinger,
  • Valeria Kovchina ,
  • Ekaterina Barvinskaya ,
  • Kirill Yumashev ,
  • Valeriy Smirnov,
  • Artem Maerle ,
  • Ivan Kozlov ,
  • Artem Shatilov ,
  • Anastasia Timofeeva ,
  • Sergey Andreev ,
  • Olesya Koloskova ,
  • Ilya Sergeev ,
  • Dmitry Trofimov ,
  • Alexander Martynov ,
  • Igor Berzin ,
  • Vladimir Gushchin,
  • Aleksey Kovalchuk ,
  • Sergei Borisevich ,
  • Rudolf Valenta,
  • Rakhim Khaitov,
  • Veronica Skvortsova
Musa Khaitov
NRC Institute of Immunology FMBA Russia

Corresponding Author:[email protected]

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Alexandra Nikonova
NRC Institute of Immunology
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Igor Shilovskiy
NRC Institute of Immunology FMBA Russia
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Ksenia Kozhikhova
NRC Institute of Immunology FMBA Russia
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Ilya Kofiadi
NRC Institute of Immunology FMBA Russia
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Lyudmila Vishnyakova
NRC Institute of Immunology FMBA Russia
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Aleksandr Nikolskii
NRC Institute of Immunology FMBA Russia
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Pia Gattinger
Medical University of Vienna
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Valeria Kovchina
NRC Institute of Immunology FMBA Russia
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Ekaterina Barvinskaya
NRC Institute of Immunology FMBA Russia
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Kirill Yumashev
NRC Institute of Immunology FMBA Russia
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Valeriy Smirnov
NRC Institute of Immunology FMBA Russia
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Artem Maerle
NRC Institute of Immunology FMBA Russia
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Ivan Kozlov
NRC Institute of Immunology FMBA Russia
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Artem Shatilov
NRC Institute of Immunology FMBA Russia
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Anastasia Timofeeva
NRC Institute of Immunology FMBA Russia
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Sergey Andreev
NRC Institute of Immunology FMBA Russia
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Olesya Koloskova
NRC Institute of Immunology FMBA Russia
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Ilya Sergeev
NRC Institute of Immunology FMBA Russia
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Dmitry Trofimov
NRC Institute of Immunology FMBA Russia
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Alexander Martynov
NRC Institute of Immunology FMBA Russia
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Igor Berzin
Federal Medico-biological Agency of Russia (FMBA Russia)
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Vladimir Gushchin
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
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Aleksey Kovalchuk
48 Central Research Institute of the Ministry of Defense of the Russian Federation
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Sergei Borisevich
48 Central Research Institute of the Ministry of Defense of the Russian Federation
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Rudolf Valenta
NRC Institute of Immunology FMBA Russia
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Rakhim Khaitov
NRC Institute of Immunology FMBA Russia
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Veronica Skvortsova
Federal Medico-biological Agency of Russia (FMBA Russia)
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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 potent anti-SARS-CoV-2 effect of siRNA both in vitro and in vivo. Methods. To identify 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 have shown 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 total lung inflammation in the animals exposed by 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.
16 Feb 2021Submitted to Allergy
17 Feb 2021Submission Checks Completed
17 Feb 2021Assigned to Editor
17 Feb 2021Reviewer(s) Assigned
21 Feb 2021Review(s) Completed, Editorial Evaluation Pending
21 Feb 2021Editorial Decision: Revise Minor
06 Mar 20211st Revision Received
10 Mar 2021Submission Checks Completed
10 Mar 2021Assigned to Editor
10 Mar 2021Reviewer(s) Assigned
14 Mar 2021Review(s) Completed, Editorial Evaluation Pending
15 Mar 2021Editorial Decision: Accept