Abstract
Abstract Tools developed by Moderna, BioNTech/Pfizer, and Oxford/Astrazeneca, among others, provide universal solutions to previously problematic aspects of drug or vaccine delivery, uptake and toxicity, portending new tools across the medical sciences. A novel method is presented based on estimating protein backbone free energy via geometry to predict effective antiviral targets, antigens and vaccine cargos that are resistant to viral mutation. This method is reviewed and reformulated in light of the recent proliferation of structural data on the SARS-CoV-2 spike glycoprotein and its mutations in multiple lineages. Key findings include: collections of mutagenic residues reoccur across strains, suggesting cooperative convergent evolution; most mutagenic residues do not participate in backbone hydrogen bonds; metastability of the glyco-protein limits the change of free energy through mutation thereby constraining selective pressure; and there are mRNA or virus-vector cargos targeting low free energy peptides proximal to conserved high free energy peptides providing specific recipes for vaccines with greater specificity than the full-spike approach. These results serve to limit peptides in the spike glycoprotein with high mutagenic potential and thereby provide a priori constraints on viral and attendant vaccine evolution. Scientific and regulatory challenges to nucleic acid therapeutic and vaccine development and deployment are finally discussed.
Highlights
Breakthrough capabilities for cellular delivery of engineered nucleic acids have overcome major hurdles [1]
Key ndings include: collections of mutagenic residues reoccur across strains, suggesting cooperative convergent evolution; most mutagenic residues do not participate in backbone hydrogen bonds; metastability of the glycoprotein limits the change of free energy through mutation thereby constraining selective pressure; and there are mRNA or virus-vector cargos targeting low free energy peptides proximal to conserved high free energy peptides providing speci c recipes for vaccines with greater speci city than the full-spike approach
Since the computations of [7] were performed before there were ample data on the SARS-CoV-2 spike in the Protein Data Bank (PDB), the rst consideration here is con rmation that the active sites of interest remain so for the more recently considered structures from SI Table 1. This is the case with the following stipulations: low pH ă6.0 disrupts bifurcated hydrogen bond high BHB free energy (BFE) especially for sites 1,2 and 3; linoleic acid binding at pH 7.0 disrupts this bifurcated high BFE of all ve sites; for site 1 even at high pH ě 7, the mutation R685S disrupts bifurcated high BFE, and D614G shifts it to nearby residues; the structure le 6x29 at pH 7.4 inexplicably has all ve bifucations disrupted
Summary
Breakthrough capabilities for cellular delivery of engineered nucleic acids have overcome major hurdles [1]. A critical question is which nucleic acid cargos to deliver for what e ect. Other aspects, such as cell-speci c uptake or translation promoters, will surely be further re ned. First applications have been the deployment of SARS-CoV-2 vaccines, whose cargo is sensibly given by nucleic acid from the virus itself. Both the Moderna and BioNTech vaccines deliver mRNA for the full spike glycoprotein, albeit a prefusion stabilized mutation K986P/V987P, called 2P, patented in 2016 in the general context of β-coronaviruses, while the adenovirus-vectored vaccines developed by Oxford and others deliver DNA instructions for the full wild-type spike
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