Fighting COVID Cytokine Storm and Targeted Nucleic Acid Therapy

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a coronavirus with a single-strand RNA (ssRNA) genome. Coronaviridae A family that includes four genera: alpha coronavirus, beta coronavirus, gamma coronavirus, and delta coronavirus. Envelope-positive ssRNA viruses are classified as Nidovirales.

Spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins are the major structural proteins required for structural stability and toxicity of SARS-CoV-2. These proteins are encoded by the positive sense ssRNA of the SARS-CoV-2 envelope.

SARS-CoV-2 binds to host cells by binding its S protein to the angiotensin converting enzyme 2 (ACE2) receptor via the receptor binding domain (RBD) of its S1 region. In addition to the ACE2 receptor, transmembrane serine protease 2 (TMPRSS2) also mediates viral entry into host cells.

study: Nucleic Acid-Based COVID-19 Therapy Targeting Cytokine Storms: Strategies to Quit Storms. Image Credit: ktsdesign / Shutterstock.com

About research

The use of microRNAs (miRNAs) to block the expression of viral proteins provides a diverse framework for controlling SARS-CoV-2 infection.In addition, some studies have shown that it is induced by coronavirus disease 2019 (COVID-19). Cytokine storm It can be reduced by targeting these miRNAs.

recently Personalized Medicine Journal Research, researchers look up the present Nucleic acidFuture possibilities considering the base treatment for COVID-19 and its method of action, and the emergence of new SARS-CoV-2 mutants of concern.

Nucleic acid-based vaccine

Nucleic acid technology is of great interest in the field of next-generation vaccines. In 1990, the first proof of concept for a DNA vaccine was carried out. This included injecting DNA or RNA molecules into the mouse model. These molecules express luciferase, beta-galactosidase, chloramphenicol acetyltransferase, and reporter genes in vivo and can be identified for up to 2 months after infection.

Since 1990, several laboratories have conducted research on vaccines, cancer immunotherapy, and immunological treatment of autoimmunity and allergic conditions using plasmid DNA and messenger RNA (mRNA). Given the increasing frequency of epidemics, advances in DNA and RNA vaccine production approaches are also important.

The first vaccine globally approved for use against COVID-19 was the Pfizer-BioNTech BNT162b2 vaccine. The Pfizer–BioNTech BNT162b2 vaccine is a nucleoside-modified RNA (modRNA) formulated with lipid nanoparticles that encodes a full-length SARS-CoV-2 S protein with two proline modifications to form a pre-fusion. Fix to.

Structural scheme of SARS-CoV-2 and its cell invasion and replication mechanism (Al-Hatamleh et al., adopted from 2020)

Many vaccinations elicit an immune response by introducing weakened or inactivated pathogenic organisms into the body. However, the Pfizer mRNA vaccine introduces genetic information from SARS-CoV-2 into host cells and induces an immune response. The mRNA from the vaccine is released into the cytoplasm of the host cell after injection, and after the viral protein is formed on the cell surface, it is degraded and destroyed.

The genetic code of the vaccine provides the host cell with “instructions” for producing the S protein. These S proteins elicit an immune response, resulting in Neutralizing antibody Robust interferon-γ (IFN-γ) and interleukin-2 (IL-2) -producing CD8 + cytotoxic T cells and CD4 + type 1 helper T (Th1) cell response, followed by any discrimination and response capability SARS -CoV-2 infection.

Nucleic acid-based therapies

There is considerable potential for the use of miRNAs to reduce cytokine storms. During active SARS-CoV-2 infection, there are multiple mechanisms available to control cytokine storms by miRNAs. For example, miRNAs can be used to manipulate the inflammatory signaling pathways involved and to regulate host miRNAs involved in inflammatory responses.

Therefore, it was proposed that miRNA mimetics could be used as cytokine storm anti-inflammatory agents by targeting the pro-inflammatory mRNA 3’UTR. Endothelial dysfunction and inflammatory responses associated with COVID-19 have been shown to be regulated by miR-26a-5p, miR-29b-3p, and miR-34a-5p. MiR-26a-5p has also been found to downregulate IL-6 and ICAM-1, but miR-29b-3p has been found to downregulate IL-4 and IL-8. All of these are underexpressed during infection. As a result, miR-26a-5p, which targets these three miRNAs, especially IL-6, and has the potential to reduce mortality, may be a possible option for reducing cytokine storms.

Implications

Vaccination with a very high percentage of the world’s population with the COVID-19 mRNA vaccine produces important data on nonviral RNA delivery, immunological response, safety, and efficacy. Researchers have leveraged these findings to integrate small interfering RNAs (siRNAs), miRNA mimetics, antagonists, and even genes into the same or similar lipid nanoparticles used in health vaccines. In the future, we may be able to develop more efficient strategies. Gene therapy.

Among the therapeutic nucleic acid (TNA) -based methods, miRNAs are highly flexible and efficient options and have great promise for reducing cytokine storms. In addition, COVID-19 is linked to many miRNAs in the host or miRNAs encoded by SARS-CoV-2, some of which can even damage the immune system. As a result, cytokine storms can be controlled by targeting these miRNAs that are directly involved in the etiology of COVID-19.