Nucleic Acid-Based Technologies Targeting Coronaviruses

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently creating a global health emergency. This crisis is driving a worldwide effort to develop effective vaccines, prophylactics, and therapeutics. Nucleic acid (NA)-based treatments hold great potential to combat outbreaks of coronaviruses (CoVs) due to their rapid development, high target specificity, and the capacity to increase druggability. Here, we review key anti-CoV NA-based technologies, including antisense oligonucleotides (ASOs), siRNAs, RNA-targeting clustered regularly interspaced short palindromic repeats-CRISPR-associated protein (CRISPR-Cas), and mRNA vaccines, and discuss improved delivery methods and combination therapies with other antiviral drugs. Coronaviruses and Nucleic Acid-Based TechnologiesCoronaviruses (CoVs) are positive-sense, single-stranded RNA (ssRNA) viruses from the Coronaviridae family in the order Nidovirales [1]. CoVs are organized into four main genera: Alpha-, Beta-, Gamma-, and Delta-coronaviruses. Many zoonotic (see Glossary) pathogenic CoVs belong to the Betacoronavirus genus, including the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 that is responsible for the current coronavirus disease 2019 (COVID-19) pandemic [2]. Other major zoonotic CoVs, such as the human coronaviruses (HCoVs), including HCoV-229E and HCoV-NL63 (in the Alphacoronavirus genus), and HCoV-OC43 and HCoV-HKU1 (in the Betacoronavirus genus), cause common colds in humans [3,4]. The polycistronic CoV RNA genome is approximately 30 kb long and encodes 14 open reading frames (ORFs). The 5′ proximal end of the genome contains two large ORFs that comprise two-thirds of the viral genome. These ORFs are translated into two large polyproteins that encode 16 nonstructural proteins (nsps) that are mainly involved in viral replication and transcription [5]. The remaining onethird of the viral genome encodes four major structural proteins: spike surface glycoprotein (S), membrane (M), nucleocapsid (N), envelope (E), and the accessory proteins, which are required for viral entry into the host cells and viral budding [6]. HighlightsNucleic-acid based therapies are worth developing against coronavirus (CoV) outbreaks because of their high specificity and rapid development.

Analysis of Emerging Variants in Structured Regions of the SARS-CoV-2 Genome

“…Similarly, hybridization-guided therapeutics, such as antisense oligonucleotides, small interfering RNAs, and CRISPR-derived drugs could potentially be targeted to the SARS-CoV-2 genome. 41 Unstructured regions in noncoding regions of the viral genome make particularly compelling targets, as access will not be blocked by RNA structure or transit of the ribosome. However, because these strategies rely on base complementarity to achieve target specificity, rapid virus evolution could prove their Achilles’ heel.…”

“… 37 , 38 There is also interest in targeting the viral genome directly, using compounds that target conserved RNA structures such as the frame-shifting pseudoknot, 39 , 40 or using informational drugs such as RNA interference triggers or antisense oligonucleotides that directly recognize the viral genome sequence. 41 As such, it is critically important that we understand how sequence and structure of viral cis-regulatory elements changes as the virus spreads. This understanding will help guide new therapeutic development to the most conserved sequences and structures, limiting the opportunity for the emergence of resistant variants in the future.…”

Lnc13728 facilitates human mesenchymal stem cell adipogenic differentiation via positive regulation of ZBED3 and downregulation of the WNT/β-catenin pathway

“…More and more studies have revealed that lncRNAs have a wide range of regulatory functions in obesity-related adipogenesis and lipid metabolism [28,29]. On the one hand, lncRNA that plays a key regulatory role in adipogenic differentiation can be used as a diagnostic marker for obesity prevention as most of the previous application cases [30][31][32]; on the other hand, although the effect of inhibiting MSC adipogenic differentiation on existing obesity remains to be clarified, whether the ASO [33,34] targeting lncRNA can be developed and utilized to intervene in obesity or at least prevent more serious obesity is still worth further study. However, most current researches based on mousederived cells or cell lines, but lncRNAs have poor conservation across species, which appears to be an inescapable barrier for comprehensively understanding the development of human adipose and future clinical application.…”

Nanotechnology‐Assisted RNA Delivery: From Nucleic Acid Therapeutics to COVID‐19 Vaccines

“…Furthermore, their safety, tolerance, and high potency have been demonstrated in numerous studies. [ 350 ] Karikó et al laid the foundation for RNA‐based vaccines in 2008. [ 351 ] In their research, the authors demonstrated that the nucleoside‐modified mRNA (modRNA) containing pseudouridines is translated more efficiently than unmodified mRNA in vitro, particularly in primary mammalian dendritic cells and in vivo in mice.…”