Developing Cytokine Storm-Sensitive Therapeutic Strategy in COVID-19 Using 8P9R Chimeric Peptide and Soluble ACE2

Abstract

Currently, the COVID-19 pandemic is an international challenge, largely due to lack of effective therapies. Pharmacotherapy has not yet been able to find a definitive treatment for COVID-19. Since SARS-CoV-2 affects several organs, treatment strategies that target the virus in a wider range are expected to be ultimately more successful. To this end, a two-step treatment strategy has been presented. In the first phase of the disease, when the patient is newly infected with the virus and the cytokine storm has not yet been developed, a chimeric peptide is used to inhibit virus entry into the host cell cytosol (by inhibiting endosomal pH acidification) and viral replication. After the virus entry and decrease of angiotensin converting enzyme 2 (ACE2) level, some people are unable to properly compensate for the ACE2 pathway and progress toward the cytokine storm. In the beginning of the cytokine storm, sACE2 protein is very effective in regulating the immune system toward the anti-inflammatory pathway, including M2 macrophages. Hence, the genes of 8P9R chimeric peptide and sACE2 would be inserted in an episomal vector with a separate promoter for each gene: the chimeric peptide gene promoter is a CMV promoter, while the sACE2 gene promoter is a NF-κB-sensitive promoter. The NF-κB-sensitive promoter induces the expression of sACE2 gene soon after elevation of NF-κB which is the main transcription factor of inflammatory genes. Thus, as the expression of inflammatory cytokines increases, the expression of sACE2 increases simultaneously. In this condition, sACE2 can prevent the cytokine storm by inhibiting the pro-inflammatory pathways. To deliver the designed vector to the target cells, mesenchymal stem cell-derived (MSC-derived) exosome-liposome hybrids are used. Herein, the strategy can be considered as a personalized clinical therapy for COVID-19, that can prevent morbidity and mortality in the future.

Angiotensin II Type I Receptor (AT1R): The Gate towards COVID-19-Associated Diseases

“…This could be explained by the diverse expression of ACE2 receptor and TMPRSS2 in nasal goblet secretory cells, lung alveolar epithelial type II cells, colonocytes, cholangiocytes, pancreatic β-cells, GI epithelial cells, and renal proximal tubules and podocytes [ 38 ]. All of these exaggerated reactions in COVID-19 patients can lead to multiorgan failure and death [ 5 , 39 ] ( Figure 3 ).…”

“…The acute respiratory disease caused by SARS-CoV-2 can range from an asymptomatic form to a severe acute respiratory distress syndrome (ARDS). Multiorgan dysfunction and failure are thus common as a result of increased vascular permeability, inflammation, and blood clot formation (coagulation), which eventually leads to mortality [ 5 ]. Until now, five SARS-CoV-2 variants have been identified, and the latest variant (B.1.1.529) was designated as omicron by the world health organization (WHO) on 26 November 2021.…”

“…The membrane-bound angiotensin-converting enzyme 2 (ACE2), a significant component of the renin–angiotensin system (RAS), is the human site of SARS-CoV-2 entry into host cells [ 5 , 7 ]. ACE2 is a monocarboxypeptidase expressed on the surface of a wide variety of different cell types, including epithelial cells lining the respiratory tract, cardiac fibroblasts, cardiomyocytes, endothelial cells, vascular smooth muscle cells (VSMCs), kidneys, intestine, and in the central nervous system (CNS) [ 5 , 8 ]. After the S-protein binding to ACE2, a membrane protease (TMPRSS2) alters the S-protein, allowing the cell membrane to fuse with the viral envelope.…”

“…After the S-protein binding to ACE2, a membrane protease (TMPRSS2) alters the S-protein, allowing the cell membrane to fuse with the viral envelope. Therefore, this will be reflected by the downregulation of ACE2 following the viral infection [ 5 , 9 ]. Once in the cytoplasm, the viral genome codes for the synthesis of proteins necessary for the replication and spread of SARS-CoV-2 [ 9 ].…”

“…Moreover, ACE2 degrades Ang II to Ang-(1–7), thereby reducing Ang II effects on vasoconstriction, sodium retention, and fibrosis [ 11 ]. As a result, decreased ACE2 levels following SARS-CoV-2 infection may lead to (i) Ang II upregulation, resulting in classical RAS axis overactivity and (ii) Ang-(1–7) depletion, reducing the activity of the protective alternative RAS axis [ 5 , 10 ] ( Figure 1 ).…”