Abstract
The worldwide pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unprecedented and the impact on public health and the global economy continues to be devastating. Although early therapies such as prophylactic antibodies and vaccines show great promise, there are concerns about the long-term efficacy and universal applicability of these therapies as the virus continues to mutate. Thus, protein-based immunogens that can quickly respond to viral changes remain of continued interest. The Spike protein, the main immunogen of this virus, displays a highly dynamic trimeric structure that presents a challenge for therapeutic development. Here, guided by the structure of the Spike trimer, we rationally design new Spike constructs that show a uniquely high stability profile while simultaneously remaining locked into the immunogen-desirable prefusion state. Furthermore, our approach emphasizes the relationship between the highly conserved S2 region and structurally dynamic Receptor Binding Domains (RBD) to enable vaccine development as well as the generation of antibodies able to resist viral mutation.
Highlights
The Coronavirus Disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1,2,3] has impacted ~100 million people worldwide and responsible for ~4 million deaths to date, according to the World Health Organization (WHO).The sudden SARS-CoV-2 virus outbreak triggered an unprecedented response from the scientific community to halt this public health crisis
In order to explore the impact of receptor binding domain (RBD) motion on the Spike trimer and prefusion status, we investigated the insertion of possible covalent disulfide bonds with the express goal of crosslinking domains in the S1 subunit
Prefusion stabilization through the insertion of two proline mutations was shown to be successful in preventing postfusion transition in the SARS-CoV and MERS-CoV Spike proteins [22], and a similar SARS-CoV-2 Spike design serves as the antigen for the recent COVID-19 vaccines [38, 39]
Summary
The Coronavirus Disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1,2,3] has impacted ~100 million people worldwide and responsible for ~4 million deaths to date, according to the World Health Organization (WHO).The sudden SARS-CoV-2 virus outbreak triggered an unprecedented response from the scientific community to halt this public health crisis. Much of the early discovery efforts were set on similarities between this emerging virus and previous members in the betacoronavirus sub-family like SARS-CoV or MERS-CoV [4,5,6]. An example of this is the Spike (S) glycoprotein. The SARS-CoV-2 Spike protein must undergo a Rational Design of Spike Proteins considerable quaternary re-arrangement (pre- and postfusion) to enable the binding of the receptor binding domain (RBD) to the angiotensin converting enzyme 2 (ACE2) on the cell surface [5, 8, 9]. Attempts to use the isolated RBD or an unstable Spike trimer as an immunogen may lead to the selection of non-neutralizing antibodies or ineffective vaccines [11,12,13]
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