Abstract
SARS-CoV-2, or COVID-19, has a devastating effect on our society, both in terms of quality of life and death rates; hence, there is an urgent need for developing safe and effective therapeutics against SARS-CoV-2. The most promising strategy to fight against this deadly virus is to develop an effective vaccine. Internalization of SARS-CoV-2 into the human host cell mainly occurs through the binding of the coronavirus spike protein (a trimeric surface glycoprotein) to the human angiotensin-converting enzyme 2 (ACE2) receptor. The spike-ACE2 protein–protein interaction is mediated through the receptor-binding domain (RBD) of the spike protein. Mutations in the spike RBD can significantly alter interactions with the ACE2 host receptor. Due to its important role in virus transmission, the spike RBD is considered to be one of the key molecular targets for vaccine development. In this study, a spike RBD-based subunit vaccine was designed by utilizing a ferritin protein nanocage as a scaffold. Several fusion protein constructs were designed in silico by connecting the spike RBD via a synthetic linker (different sizes) to different ferritin subunits (H-ferritin and L-ferritin). The stability and the dynamics of the engineered nanocage constructs were tested by extensive molecular dynamics simulation (MDS). Based on our MDS analysis, a five amino acid-based short linker (S-Linker) was the most effective for displaying the spike RBD over the surface of ferritin. The behavior of the spike RBD binding regions from the designed chimeric nanocages with the ACE2 receptor was highlighted. These data propose an effective multivalent synthetic nanocage, which might form the basis for new vaccine therapeutics designed against viruses such as SARS-CoV-2.
Highlights
The worldwide pandemic caused by SARS-CoV-2 is a very serious threat to public health
The findings from this study suggest that synthetic SARS-CoV-2 spike receptor-binding domain (RBD)–ferritin nanocages are highly dynamic in nature, and determined the optimum length of the linker that is necessary for holding
The secondary structures (α-helices, β-sheets/strands, and loops) of the SARS-CoV-2 spike RBD and the H-/L-ferritin cages can acquire a high degree of freedom in a solvent environment during molecular dynamics simulation (MDS), and changes in their secondary structures can illustrate the stability of the designed chimeric construct
Summary
The worldwide pandemic caused by SARS-CoV-2 is a very serious threat to public health. There have been over 95.6 million confirmed cases of COVID-19, and over. 2.04 million casualties reported worldwide [1]. Several strategies have emerged since its outbreak to control this deadly virus; the most promising strategy and long-term solution is to develop an effective vaccine. Vaccine scaffolds can be of different types; for the SARS-CoV-2 treatment, protein subunit vaccines and genetically encoded nucleic acid vaccines are the most effective [2]. SARS-CoV-2 is a classic viral nanostructure consisting of nuclear material (RNA genome) surrounded by several (four) coat proteins including the SARS-CoV-2 spike (S) glycoprotein (Figure 1) [3]. Among different coat proteins from SARS-CoV-2, the spike protein is the most crucial for the host angiotensin-converting enzyme 2 (ACE2)
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