Preprint Concept Paper Version 1 Preserved in Portico This version is not peer-reviewed

Think Different with RNA Therapy: Can Antisense Oligonucleotides Be Used to Inhibit Replication and Transcription of SARS-Cov-2?

Version 1 : Received: 21 April 2020 / Approved: 23 April 2020 / Online: 23 April 2020 (11:30:39 CEST)

How to cite: Barrey, E.; Burzio, V.; Dhorne-Pollet, S.; Eléouët, J.; Delmas, B. Think Different with RNA Therapy: Can Antisense Oligonucleotides Be Used to Inhibit Replication and Transcription of SARS-Cov-2?. Preprints 2020, 2020040412 (doi: 10.20944/preprints202004.0412.v1). Barrey, E.; Burzio, V.; Dhorne-Pollet, S.; Eléouët, J.; Delmas, B. Think Different with RNA Therapy: Can Antisense Oligonucleotides Be Used to Inhibit Replication and Transcription of SARS-Cov-2?. Preprints 2020, 2020040412 (doi: 10.20944/preprints202004.0412.v1).

Abstract

The severity of the global COVID-19 pandemic, with a high transmission rate, 2.6-4.7% lethality and a huge economic impact, poses an urgent need for efficient medical treatments and vaccines. Currently, there are only non-specific treatments to assist the patients in acute respiratory distress during the inflammatory step following the preliminary infection by SARS-CoV-2. Clinical trials of drug repurposing were quickly launched at the international level. Specific treatments such as the transfusion of plasma from patients who have recovered into infected patients or the use of specific inhibitors of the viral RNA-polymerase complex are promising strategies to block infection. To complete the therapeutic arsenal, we believe that the opportunity of targeting the SARS-CoV-2 genome by RNA therapy should be deeply investigated. In the present paper, we propose to design specific antisense oligonucleotides targeting transcripts encoding viral proteins associated to replication and transcription of SARS-CoV-2, aiming to block infection. We designed antisense oligonucleotides targeting the genomic 5’ untranslated region (5’-UTR), open reading frames 1a and 1b (ORF1a and ORF1b) governing expression of the replicase/transcriptase complex, and the gene N encoding the nucleoprotein that is genome-associated. To maximize the probability of efficiency, we predicted the antisense oligonucleotides by using two design methods: i) conventional antisense oligonucleotides with 100% phosphorothioate modifications (ASO); ii) antisense locked nucleic acids GapmeR. After binding the viral RNA target, the hetero-duplexes antisense oligonucleotide-RNA are cleaved by RNAse H1. Nine potent ASO candidates were found and we selected five of them targeting ORF1a (3), ORF1b (1) and N (1). Nine GapmeR candidates were predicted with excellent properties and we retained four of them targeting 5’-UTR (1), ORF1a (3), ORF1b (1) and N (1). The most potent GapmeR candidate targets the 5’-UTR, a key genomic domain with multiple functions in the viral cycle. By this open publication, we are pleased to share these in silico results with the scientific community in hopes of stimulating innovation in translational research in order to fight the unprecedented COVID-19 pandemic. These antisense oligonucleotide candidates should be now experimentally evaluated.

Subject Areas

coronavirus; COVID-19; antisense oligonucleotide; ASO; LNA GapmeR

Comments (1)

Comment 1
Received: 1 May 2020
Commenter: Barrey Eric and co-authors
The commenter has declared there is no conflict of interests.
Comment: Important remark, the 1st May 2020: an update of the paper and in particular Table 1, Table S1 and Table 2 will be done very soon. This update will correct an error of ASO PTO-modified sequences in Table 1 and Table S1. Table 2 will be updated with more information about the LNA GapmeR sequences. These revisions of the results do not change the conclusions of the paper.
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