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A scalable pipeline for SARS-CoV-2 replicon construction based on de-novo synthesis

View ORCID ProfileAhmet C. Berkyurek, Elian Lee, View ORCID ProfileOmer Weissbrod, View ORCID ProfileRoni Rasnic, Ilaria Falciatori, Siyuan Chen, View ORCID ProfileYaniv Erlich
doi: https://doi.org/10.1101/2022.02.05.478644
Ahmet C. Berkyurek
1Eleven Therapeutics, Cambridge, UK
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Elian Lee
2Twist Bioscience, South San Francisco, CA
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Omer Weissbrod
1Eleven Therapeutics, Cambridge, UK
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Roni Rasnic
1Eleven Therapeutics, Cambridge, UK
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Ilaria Falciatori
1Eleven Therapeutics, Cambridge, UK
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Siyuan Chen
2Twist Bioscience, South San Francisco, CA
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Yaniv Erlich
1Eleven Therapeutics, Cambridge, UK
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  • For correspondence: yaniv@eleventx.com
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Abstract

Replicons are synthetic viral RNA molecules that recapitulate the self-replicating activities of the virus but are missing its infectivity potential. Here, we report on a scalable pipeline to generate a replicon of any SARS-CoV-2 strain using de-novo synthesis. Our pipeline relies only on publicly available sequencing data without requiring access to any material, simplifying logistical and bureaucratic issues of sample acquisition. In addition, our system retains the nucleotide sequence of most of the SARS-CoV-2 full genome and therefore better captures its underlying genomic and biological functions as compared to the popular pseudotypes or any replicon system published to-date. We utilized our system to synthesize a SARS-CoV-2 non-infectious version of the Beta strain. We then confirmed that the resulting RNA molecules are non-infectious and safe to handle in a BSL2/CL2 facility. Finally, we show that our replicon can be specifically inhibited by molnupiravir and RNAi treatments, demonstrating its utility for drug research and development.

Competing Interest Statement

A.C.B, O.W., R.R., I.F., and Y.E. are employees of Eleven Therapeutics. E.L. and S.C. are employees of Twist Bioscience. Y.E. is a part time employee of the Reichman University (IDC Herzliya) and of MyHeritage LTD. He serves as an SAB member of ArcBio.

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 February 05, 2022.
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A scalable pipeline for SARS-CoV-2 replicon construction based on de-novo synthesis
Ahmet C. Berkyurek, Elian Lee, Omer Weissbrod, Roni Rasnic, Ilaria Falciatori, Siyuan Chen, Yaniv Erlich
bioRxiv 2022.02.05.478644; doi: https://doi.org/10.1101/2022.02.05.478644
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A scalable pipeline for SARS-CoV-2 replicon construction based on de-novo synthesis
Ahmet C. Berkyurek, Elian Lee, Omer Weissbrod, Roni Rasnic, Ilaria Falciatori, Siyuan Chen, Yaniv Erlich
bioRxiv 2022.02.05.478644; doi: https://doi.org/10.1101/2022.02.05.478644

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