Features of SARS-COV-2 infection and directions of drug and vaccine creation

Abstract

Introduction: Until the beginning of the 21st century human coronaviruses were known as the cause of typical seasonal аcute respiratory disease. Highly pathogenic coronaviruses were identified as the cause of severe acute respiratory syndrome (SARS) with high mortality in 2002 – SARS-CoV, and then in 2013 as the causative agents of Middle East respiratory syndrome – MERS-CoV. They have caused severe respiratory disease in humans because of their ability to adapt to the host, increasing affinity for human airway receptors. The emergence a new coronavirus in 2019 caused a rapid increase in the incidence of severe acute respiratory syndrome and turned into a pandemic. Background: The new coronavirus SARS-CoV-2, which causes Covid-19 (coronavirus infection disease), was first detected in December 2019 in Wuhan, the capital of Hubei province, from where it quickly spread to China and continued to spread to Italy and other countries of Europe and after around the world, the number of confirmed new cases is increasing daily. Rationale: Coronaviruses are members of the order Nidovirales of the family Coronaviridae and divided into 4 genera: α- and β-coronavirus, which infect only mammals, and γ- and δ-coronavirus, which mainly affect birds. The central place is occupied by the genus β-coronavirus, which includes especially dangerous pathogens of lethal human pneumonia – SARS-CoV, MERS-CoV, SARS-CoV2. In turn, β-coronavirus divided into four subgenres: A, B, C, D. SARS-CoV-2 is β-coronavirus, subgroup B, Sarbecovirus. Coronaviruses affecting humans currently have 7 species. They divide into 2 groups. 1^st group  has 4 common types of coronaviruses that cause about 15% of typical seasonal SARS: HCoV-229E, NL63, OC43 and HKU1. Usually these types cause mild forms of upper respiratory tract diseases in children (and less often in adults), but in some cases (like other SARS viruses) cause interstitial pneumonia (in newborns, children with immunodeficiency, people with cancer, patients who take immunosuppressive therapy, the elderly with heart failure and chronic lung disease). 2^nd group has 3 types of coronaviruses, which in a large percentage of cases SARS. 1. SARS-CoV – the epidemic began in China in November 2002 from live animal markets in Foshan (Guangdong Province), spreading to Asia and the world. Considered, horseshoe bats can be the natural reservoir of SARS-CoV. SARS-CoV affected 32 countries for 9 months, 8096 people became ill, of which 774 died (9% mortality). No new cases of SARS-CoV have been report since 2004. 2. Another type of coronavirus that caused SARS in humans, MERS-CoV, first detected in Saudi Arabia in 2012. Сonsidered bats can be the natural reservoir of MERS-CoV, and single-humped camels can be vectors. MERS-CoV has been founding in patients in 27 countries, mainly in the Middle East, and remains endemic in many of them due to circulation in camels. The last outbreak of MERS occurred in South Korea in 2015, where the virus was imported from Kuwait (186 became ill and 33 died – the elderly). As of November 2019, MERS-CoV caused 858 deaths out of 2494 laboratory-confirmed cases (33% mortality). 3. SARS-CoV-2, like SARS-CoV and MERS-CoV, can cause severe respiratory disease with a high mortality rate. Horseshoe bats considered the natural reservoir of SARS-CoV2 (as well as SARS-CoV). There are two versions for SARS-CoV2: the first is that is bat coronavirus and it has spread from the seafood market, can crossed the interspecies barrier and become pathogenic to humans; second, that during an experiment at the Institute of Virology in Wuhan, the coronavirus accidentally struck an employee in an aerosol, who became the "first patient". Discussion: The virion of coronaviruses is covered with a lipid shell that clearly visible on electron microscopic images club-shaped spikes length of 10 nm. Coronaviruses contain a positive single-stranded RNA genome with a length of 26 to 32 thousand nucleotides (the largest known RNA virus) and four structural proteins – spike (S), envelope (E), membrane (M) and nucleocapsid (N). Protein S binds to target cell receptors and triggers the infectious process, protein M plays a role in shell formation and virion formation, and protein E forms pentameric ion channels that destroy cell membranes during viral budding. SARS-CoV-2 uses as receptors for cell penetration CD147 – glycoprotein and angiotensin converting enzyme type 2 (angiotensin converting enzyme 2 – ACE2). CD147 expressed in the cell membrane of epithelial and endothelial cells and T lymphocytes. Monoclonal antibodies against CD147 prevent infection of SARS-CoV2 cells in vitro. Analysis of cell samples for the presence of RNA sequences SARS-CoV-2 reveals significant RNA transcription in the nasal epithelium and less in the cells of the lower respiratory tract and alveolar epithelium. This suggests that the upper rather than the lower respiratory tract is the initial site of SARS-CoV-2 infection. ACE2 localized in type I and II pneumocytes, vascular endothelial cells and enterocytes (therefore symptoms from the respiratory tract are often accompanied by symptoms from the gastrointestinal tract – nausea, diarrhea, etc.). SARS-CoV2 infection leads to cytopathic effects, including apoptosis, cell lysis, and syncytium formation in lung tissue. After penetration into the host cell, the SARS-CoV-2 genome attaches to the ribosomes, leading to the translation of viral polyproteins, which subsequently processed by viral proteolytic enzymes. As a result, of proteolysis the protease-mediated virus 3CLpro (chymotrypsin-like protease) and PLpro (papain-like protease), polyproteins are broken down into smaller components, which plays a major role in mediating the replication and transcription of viruses and promotes infection. Another RdRp (RNA-dependent RNA-polymerase) enzyme, replicase, is important for viral genome replication and products of new virions. Therefore, these enzymes can considered as potential drug targets for the development of therapeutic agents, as they are crucial for the survival, replication and transmission of SARS-CoV-2. Therapeutic strategies is using for the treatment of Covid-19 mainly divided into immune and antiviral. S, E, M, N proteins, two replicase isoforms (RdRp1a and RdRp1ab) and proteases (3CLpro and PLpro) can be considere as potential targets for drugs and vaccines against SARS-CoV-2. Despite the many directions in the search the effective drugs for treatment Covid-19, today the most effective strategy in therapy is access to oxygen and well-staffed supportive care reduces mortality more than any medicinal product. Conclusion.  The sudden appearance of SARS-CoV-2 and the pandemic caused by this virus have posed a threat to the security of the global health system. The scientific community around the world is working hard to find effective drugs and vaccines against the new coronavirus. In an effort to find the cure for Covid-19, WHO has developed the SOLIDARITY concept, an international clinical trial as a common global platform for improving scientific links and accelerating information exchange. On the base of Mechnicov institute of microbiology and immunology National academy of medical sciences of Ukraine also began the study of the peculiarities of immunity Covid-19 for further development the therapeutic and vaccine strategies.

DOI: 10.5281/zenodo.4382122