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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. Highlights Nucleic-acid based therapies are worth developing against coronavirus (CoV) outbreaks because of their high specificity and rapid development. Several key therapeutic nucleic acid (TNA) strategies, including antisense oligonucleotides (ASOs), siRNA, and RNA-targeting clustered regularly interspaced short palindromic repeats-CRISPR-associated protein (CRISPR-Cas) technologies targeting the viral genome are potentially applicable to combat CoVs. mRNA vaccines are attractive candidates to control CoV outbreaks with rapid/easy manufacturing, high potency, and safety. Optimal therapeutic cocktails comprising different TNAs or TNAs with other antiviral agents could act on multiple targets simultaneously, thereby enhancing antiviral effects and reducing risk of drug resistance. Lipid-ASO (LASO) nanomicelles enable cellular self-uptake and can be conjugated with antiviral molecules, providing promising anti-CoV combinational therapeutics that can be delivered directly to the lungs by aerosol. Advancement in chemical modifications and delivery vehicles remarkably enhance stability and pharmacokinetic profile of TNAs, facilitating clinical application of numerous TNAs; however, more studies on optimal chemical manufacturing and delivery methods improving safety and efficiency for TNAs are needed.

SUBMITTER: Le T

PROVIDER: S-EPMC7691141 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Project description:The innate immune system provides the first line of defense against pathogen infection though also influences pathways involved in cancer immunosurveillance. The innate immune system relies on a limited set of germ line-encoded sensors termed pattern recognition receptors (PRRs), signaling proteins and immune response factors. Cytosolic receptors mediate recognition of danger damage-associated molecular patterns (DAMPs) signals. Once activated, these sensors trigger multiple signaling cascades, converging on the production of type I interferons and proinflammatory cytokines. Recent studies revealed that PRRs respond to nucleic acids (NA) released by dying, damaged, cancer cells, as danger DAMPs signals, and presence of signaling proteins across cancer types suggests that these signaling mechanisms may be involved in cancer biology. DAMPs play important roles in shaping adaptive immune responses through the activation of innate immune cells and immunological response to danger DAMPs signals is crucial for the host response to cancer and tumor rejection. Furthermore, PRRs mediate the response to NA in several vaccination strategies, including DNA immunization. As route of double-strand DNA intracellular entry, DNA immunization leads to expression of key components of cytosolic NA-sensing pathways. The involvement of NA-sensing mechanisms in the antitumor response makes these pathways attractive drug targets. Natural and synthetic agonists of NA-sensing pathways can trigger cell death in malignant cells, recruit immune cells, such as DCs, CD8+ T cells, and NK cells, into the tumor microenvironment and are being explored as promising adjuvants in cancer immunotherapies. In this minireview, we discuss how cGAS-STING and RIG-I-MAVS pathways have been targeted for cancer treatment in preclinical translational researches. In addition, we present a targeted selection of recent clinical trials employing agonists of cytosolic NA-sensing pathways showing how these pathways are currently being targeted for clinical application in oncology.

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Nucleic Acid-Based Technologies Targeting Coronaviruses

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