RESUMO
Immune responses to SARS-CoV-2 primarily target the receptor binding domain of the spike protein, which continually mutates to escape acquired immunity. Other regions in the spike S2 subunit, such as the stem helix and the segment encompassing residues 815-823 adjacent to the fusion peptide, are highly conserved across sarbecoviruses and are recognized by broadly reactive antibodies, providing hope that vaccines targeting these epitopes could offer protection against both current and emergent viruses. Here we employed computational modeling to design scaffolded immunogens that display the spike 815-823 peptide and the stem helix epitopes without the distracting and immunodominant RBD. These engineered proteins bound with high affinity and specificity to the mature and germline versions of previously identified broadly protective human antibodies. Epitope scaffolds interacted with both sera and isolated monoclonal antibodies with broadly reactivity from individuals with pre-existing SARS-CoV-2 immunity. When used as immunogens, epitope scaffolds elicited sera with broad betacoronavirus reactivity and protected as "boosts" against live virus challenge in mice, illustrating their potential as components of a future pancoronavirus vaccine.
RESUMO
Genetic oscillators have long held the fascination of experimental and theoretical synthetic biologists alike. From an experimental standpoint, the creation of synthetic gene oscillators represents a yardstick by which our ability to engineer synthetic gene circuits can be measured. For theorists, synthetic gene oscillators are a playground in which to test mathematical models for the dynamics of gene regulation. Historically, mathematical models of synthetic gene circuits have varied greatly. Often, the differences are determined by the level of biological detail included within each model, or which approximation scheme is used. In this review, we examine, in detail, how mathematical models of synthetic gene oscillators are derived and the biological processes that affect the dynamics of gene regulation.