Synthesis of Chimeric Oligonucleotides Having Modified Internucleotide Linkages via an Automated H-Phosphonate/Phosphoramidite Approach

AbstractThere is an urgent need for effective antiviral drugs to alleviate the current COVID-19 pandemic. Here, we rationally designed and developed chimeric antisense oligonucleotides to degrade envelope and spike RNAs of SARS-CoV-2. Each oligonucleotide comprises a 3’ antisense sequence for target recognition and a 5’-phosphorylated 2’-5’ poly(A)4 for guided ribonuclease L (RNase L) activation. Since RNase L can potently cleave single strand RNA during innate antiviral response, the improved degradation efficiency of chimeric oligonucleotides was twice as much as classic antisense oligonucleotides in Vero cells, for both SARS-CoV-2 RNA targets. In pseudovirus infection models, one of chimeric oligonucleotides targeting spike RNA achieved potent and broad-spectrum inhibition of both SARS-CoV-2 and its recently reported N501Y and/or ΔH69/ΔV70 mutants. These results showed that the constructed chimeric oligonucleotides could efficiently degrade pathogenic RNA of SARS-CoV-2 facilitated by immune activation, showing promising potentials as antiviral nucleic acid drugs for COVID-19.

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Synthesis and alternate-stranded triplex forming ability of novel - chimeric oligonucleotides bearing an intercalator-conjugated nucleobase

Nucleic Acids Symposium Series ◽

10.1093/nass/48.1.207 ◽

2004 ◽

Vol 48 (1) ◽

pp. 207-208

Author(s):

A. Z. Azam

Keyword(s):

Chimeric Oligonucleotides

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Solid-Phase Synthesis of Phosphorothioate/Phosphonothioate and Phosphoramidate/Phosphonamidate Oligonucleotides

Molecules ◽

10.3390/molecules24101872 ◽

2019 ◽

Vol 24 (10) ◽

pp. 1872 ◽

Cited By ~ 1

Author(s):

Ondřej Kostov ◽

Radek Liboska ◽

Ondřej Páv ◽

Pavel Novák ◽

Ivan Rosenberg

Keyword(s):

Solid Phase Synthesis ◽

Solid Phase ◽

The Novel ◽

Phase Synthesis ◽

Chimeric Oligonucleotides ◽

Modified Oligonucleotide

We have developed a robust solid-phase protocol which allowed the synthesis of chimeric oligonucleotides modified with phosphodiester and O-methylphosphonate linkages as well as their P-S and P-N variants. The novel O-methylphosphonate-derived modifications were obtained by oxidation, sulfurization, and amidation of the O-methyl-(H)-phosphinate internucleotide linkage introduced into the oligonucleotide chain by H-phosphonate chemistry using nucleoside-O-methyl-(H)-phosphinates as monomers. The H-phosphonate coupling followed by oxidation after each cycle enabled us to successfully combine H-phosphonate and phosphoramidite chemistries to synthesize diversely modified oligonucleotide strands.

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