PMC:7435837 / 6185-12165 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7435837","sourcedb":"PMC","sourceid":"7435837","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7435837","text":"3. Potential Targets for Drug Development against Coronaviruses\nIt has been shown at the time of writing that ACE-2 receptors in the lungs are specific targets for SARS-CoV-2 spike proteins [15]. It has been found that lung parenchyma must be in the differentiated state of the cell cycle and must express the ACE-2 receptor on the apical side, i.e., the site of the first contact with air, of the parenchyma [16,17,18,19]. It is no surprise therefore that the SARS, MERS, and SARS-CoV-2 viruses cause significant lung injury [20,21,22,23,24]. ACE-2 is also expressed to a significant extent in the gastrointestinal tract (GIT) [25] which accounts for the GIT symptoms that appeared in SARS-CoV patients and currently in SARS-CoV-2 infected patients [26].\nCurrent pharmaceutical efforts against coronaviruses aim to interfere with the binding of the viral glycans in their spike proteins to potential host cell receptors. The drug umifenovir has been shown to prevent the fusion of viral S-proteins with the host cell ACE-2 receptors, therefore excluding cell entry of the virus. However, umifenovir was clinically inefficient to improve the Covid-19 disease outcome [27].\nA contributing membrane-bound enzyme that facilitates spike protein entry via ACE-2 receptors is the TMPRSS2 serine protease. This protease primes the coronavirus spike protein for entry by cleaving protein domains that increase the interaction with host cell membranes that result in membrane fusion [28]. It was also suggested that TMPRSS2 cleaves ACE-2 sites that promote the affinity for the viral spike protein, hence enhances cell entry [29].\nAnother possible target for treatment is the inhibition of the synthesis of the required saccharides that are incorporated in the host cell glycoproteins. Several quinine derivatives showed that these saccharide moieties known as sialic acids could be inhibited by drugs such as hydroxychloroquine. The quinines, therefore, decrease the number of glycan targets that could be engaged by coronaviral spike proteins to facilitate cell entry [30,31,32]. However, quinine derivatives pose significant cardiotoxicity that precludes their application as a treatment for Covid-19 [33].\nAntiretrovirals such as nelfinavir have proven to be efficient inhibitors of post-entry replication of the virions of SARS-CoV [34,35]. It has been found that protease inhibitors used in SARS and MERS studies prevented the cleavage and activation of spike proteins following the translation of precursor polypeptides from the viral RNA [36,37]. RNA is a vital step towards the ultimate formation of the structural protein of new viruses [34]. Ritonavir and lopinavir [38] have shown some good activity against the SARS-CoV protein cleavage that ultimately prevents spike proteins from forming. Some investigated drugs have been reviewed as protease inhibitors against coronaviruses and the reader is referred to the publication by Adedeji et al. [39]. Figure 2 shows the currently identified targets for which drugs are investigated.\nVaccination efforts are attempting to create a substrate that can be recognized by dendritic cells. The dendritic cells will subsequently label the virus spike proteins with coronavirus specific CD4+/CD8+ peptides. These specifically loaded particles will then be presented to T-cells that interact with T-lymphocyte dependent antigens. This interaction results in the induction of B-lymphocytes that produces antibodies that can recognize the spike proteins of coronaviruses to afford phagocytosis and destructions of the virus. It is also expected that memory T-cells will form which could result in long-term immunity when these cells are replicated when a spike protein can be recognized by dendritic or other immune cells. The carbohydrate-based vaccine holds promise to present recognizable glycan arrays that are representative of the targeted pathogens [41].\nVery recently, several targets have been identified for the development of SARS-CoV-2 vaccines that have been identified based on the similarity of the virus to a previously encountered coronavirus, SARS-CoV [42]. It has been proven that many of the human pathogenic coronaviruses share a significant genomic overlap of more than 99.9% and this provides the basis for developing vaccines from a previously encountered coronavirus infection before SARS-CoV-2 [15,43]. The Middle East respiratory syndrome-related coronavirus, MERS-CoV, and SARS-CoV form part of these β-coronaviruses which wreaked havoc in the last two decades [44].\nTherefore, one of the most promising targets is the characterization of spike protein epitopes that can be recognized by immune cells such as B- and T-cells. Some form of replication of this spike protein epitope should, therefore, be developed and this will hopefully provide the antigens which can bind to, for example, B- or T-cell antibodies and alert the immune system to coronaviruses [44,45]. A recombinant vaccination approach could be demonstrated by expressing the receptor-binding domain [46] of SARS-CoV spike protein in an adenovirus. This recombinant adenovirus was administered nasally and T-cells showed a significant immune response towards the expressed spike protein-binding domain [47].\nRecombinant DNA approaches have made significant strides towards the synthesis of peptide sequences that can directly bind to spike protein epitopes. Spike proteins of the MERS-CoV were neutralized in this way [48,49]. The spike protein antigen of the MERS-CoV was also reported and identified targets for spike protein deactivation [50].\nIt is emphasized that the discussion of chemotherapeutic and vaccination efforts is superficial and not covered in detail in this report. Of importance though is the fact that antigen-antibody interactions are a key interest in developing vaccines. This recognition mechanism is creating the prelude for the discussion of the layer-by-layer nanocoating process that will be elaborated in due 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