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An antiviral self-replicating molecular heterotroph

Anastasia Shapiro, Alexander Rosenberg, Adva Levy-Zamir, Liron Bassali, Shmulik Ittah, Almogit Abu-Horowitz, View ORCID ProfileIdo Bachelet
doi: https://doi.org/10.1101/2020.08.12.248997
Anastasia Shapiro
1Augmanity, Rehovot, Israel
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Alexander Rosenberg
1Augmanity, Rehovot, Israel
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Adva Levy-Zamir
1Augmanity, Rehovot, Israel
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Liron Bassali
1Augmanity, Rehovot, Israel
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Shmulik Ittah
1Augmanity, Rehovot, Israel
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Almogit Abu-Horowitz
1Augmanity, Rehovot, Israel
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Ido Bachelet
1Augmanity, Rehovot, Israel
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  • ORCID record for Ido Bachelet
  • For correspondence: ido@augm.com
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Abstract

We report the synthesis of a molecular machine, fabricated from nucleic acids, which is capable of digesting viral RNA and utilizing it to assemble additional copies of itself inside living cells. The machine’s body plan combines several parts that build upon the target RNA, assembling an immobile, DNA:RNA 4-way junction, which contains a single gene encoding a hammerhead ribozyme (HHR). Full assembly of the machine’s body from its parts enables the subsequent elongation of the gene and transcription of HHR molecules, followed by HHR-mediated digestion of the target molecule. This digestion converts the target to a building block suitable for participation in the assembly of more copies of the machine, mimicking biological heterotrophy. In this work we describe the general design of a prototypical machine, characterize its activity cycle and kinetics, and show that it can be efficiently and safely delivered into live cells. As a proof of principle, we constructed a machine that targets the Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) GP64 gene, and show that it effectively suppresses viral propagation in a cell population, exhibiting predator/prey-like dynamics with the infecting virus. In addition, the machine significantly reduced viral infection, stress signaling, and innate immune activation inside virus-infected animals. This preliminary design could control the behavior of antisense therapies for a range of applications, particularly against dynamic targets such as viruses and cancer.

Competing Interest Statement

All authors are employees and/or shareholders in Augmanity, a research company based in Rehovot, Israel, developing technologies reported in this paper, and are listed as inventors on patents related to technologies reported in this paper. The authors declare no non-financial interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 14, 2020.
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An antiviral self-replicating molecular heterotroph
Anastasia Shapiro, Alexander Rosenberg, Adva Levy-Zamir, Liron Bassali, Shmulik Ittah, Almogit Abu-Horowitz, Ido Bachelet
bioRxiv 2020.08.12.248997; doi: https://doi.org/10.1101/2020.08.12.248997
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An antiviral self-replicating molecular heterotroph
Anastasia Shapiro, Alexander Rosenberg, Adva Levy-Zamir, Liron Bassali, Shmulik Ittah, Almogit Abu-Horowitz, Ido Bachelet
bioRxiv 2020.08.12.248997; doi: https://doi.org/10.1101/2020.08.12.248997

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