The article below was originally published on May 1 2020, but it points out the power of mutation in the Covid-19 virus so we have republished it.
Below is an excerpt from a scientific lab report, you can read the entire article here. At the bottom is underlined text where it is clearly stated that 'any variation' in the RNA" will render a treatment ineffective, plus the virus creates mutation paths of replicating proteins each of which has to be treated, but the problem being, the virus creates 'parallel routes' and testing shows more than one mechanism of their creation. This makes any specific vaccine to be extremely difficult to synthesise accurately given the internal robust capacity for bio mutations and in effectiveness one would have to say it must be relatively small.
1.5. Human protein targets for design of therapeutics against COVID-19
The immune system by its nature can make its own adjustments to recognize pathogens and vaccines, but designing some kind of therapeutic antagonist against virus binding to the lung cells requires rather more consideration about what human protein the spike protein is binding. Bioinformatics as the study of biosequences is a powerful tool, but it is well known that having the detailed three dimensional structure of the human protein target for a potential new pharmaceutical agent, or to which a virus attaches, is a great benefit to rational computer-aided design. Studies specifically investigating human protein binding and activation of previously known SARS viruses have for some years been carried out by several groups (e.g. Refs. [, , , ]). It seems reasonably well agreed that angiotensin converting enzyme type 2 (ACE2) is responsible for binding the SARS associated with the 2002 outbreak, combined with a proteolytic cleavage to activate the spike protein, for which type II transmembrane serine protease (TMPRSS2) is the current popular candidate . Several three dimensional structures are known for ACE2 complexed with SARS spike protein e.g. protein data bank (PDB) entry (6ACG) and of variants of the latter (e.g. TMPRSS2 protein data bank entry 2OQ5).
However, the full story involving human cell surface proteins (with which SARS-CoV-2 interacts in order to infect and replicate) is possibly not quite as firmly established at the time of this present study as some summaries would suggest. The origin of the general problem for a more detailed conformational chemistry approach is that diversity of genome and means of infecting cells are readily generated in nature in the case of different virus hosts, virus strains, and species jumps, and it is long established that the binding shows variation in the receptors used that correspond to viral groups. There have been alternative proposed candidates for initial binding receptors, e.g. carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), and various dipeptidyl peptidases. Highly virulent coronaviruses that form syncytia between cells can even spread in a receptor-independent fashion. Even when an initial binding receptor such as ACE2 is identified for a coronavirus, initial uncertainty or enduring complexity for the rest of the entry process may be the norm. Many other human proteases present in the lung seem capable of cleaving various sites on the spike protein and which could cause its activation. For example, a variety of proteases such as trypsin, tryptase Clara, mini-plasmin, human airway trypsin-like protease (HAT), and TMPRSS2 (transmembrane protease, serine 2) are known to cleave the glycoprotein hemagglutinin (HA) of influenza A viruses as prerequisite for the fusion between viral and host cell membranes and viral cell entry. Human airway trypsin like protease (HAT), TMPRSS3, TMPRSS4, TMPRSS6 have also all been considered by SARS researchers at various stages. Other human proteins that might have similar involvement to the above in the SARS-CoV-2 case, and that are also affected by the same antagonists against the SARS-Cov-2 targets in the preceding paragraph, have also attracted the attention of researchers. The trypsin-like serine protease hepsin which has a fairly broad action and which is significantly inhibited by a diverse set of ligands, a particular example of one such binding is represented by protein data bank entry 5ce1. Even intracellular proteases could be released on cell damage resulting from the first wave of lung infection or from other disease or tissue trauma. Some variants and strains may use other, as yet unknown, proteins, or sugars, to assist entry. It is also plausible the spike protein might be activated by other proteases on exit from the epithelial lung cells, so allowing it efficiently to infect other cells. The spike glycoprotein of SARS-CoV-2 also has the so-called furin cleavage sequence (PRRARS or PRRARS), which is an extension to the so-called PIGAG motif of ref . Consistent with the present author's preferred choice of KRSFIEDLLFNKV motif, coronaviruses with high sequence homology (such as that isolated from a bat in Yunnan in 2013), lack the furin cleavage sequence. Nonetheless, because furin proteases are abundant in the respiratory tract, SARS-CoV-2 spike glycoprotein might be cleaved on exit from cells.
Even if the means of binding, activation and entry is well established for a viral strain, recall that a single RNA base difference resulting in a single amino acid residue difference could alter all that, and there also appear to be several other possibilities that the virus can exploit in parallel. Indeed, somewhat similarly, potential inhibitors of SARS entry and/or activation proposed by researchers may work by several routes in parallel, and significantly at least three mechanisms were reported in one relevant study .