Targeting SARS-CoV-2 Variants with Nucleic Acid Therapeutic Nanoparticle Conjugates

Huber, Hanah F.; Jaberi-Douraki, Majid; DeVader, Sarah; Aparicio-Lopez, Cesar; Nava-Chavez, Juliet; Xu, Xuan; Millagaha Gedara, Nuwan Indika; Gaudreault, Natasha N.; Delong, Robert K.

The emergence of SARS-CoV-2 variants is cause for concern, because these may become resistant to current vaccines and antiviral drugs in development. Current drugs target viral proteins, resulting in a critical need for RNA-targeted nanomedicines. To address this, a comparative analysis of SARS-CoV-2 variants was performed. Several highly conserved sites were identified, of which the most noteworthy is a partial homopurine palindrome site with >99% conservation within the coding region. This sequence was compared among recently emerged, highly infectious SARS-CoV-2 variants. Conservation of the site was maintained among these emerging variants, further contributing to its potential as a regulatory target site for SARS-CoV-2. RNAfold was used to predict the structures of the highly conserved sites, with some resulting structures being common among coronaviridae. An RNA-level regulatory map of the conserved regions of SARS-CoV-2 was produced based on the predicted structures, with each representing potential target sites for antisense oligonucleotides, triplex-forming oligomers, and aptamers. Additionally, homopurine/homopyrimidine sequences within the viral genome were identified. These sequences also demonstrate appropriate target sites for antisense oligonucleotides and triplex-forming oligonucleotides. An experimental strategy to investigate these is summarized along with potential nanoparticle types for delivery, and the advantages and disadvantages of each are discussed.