Developing Lectins as Inhibitors of Coronavirus Spike Proteins

项目总结/文摘

Project Summary/Abstract In late 2019, the SARS-CoV2 virus emerged as a global pandemic, causing the severe respiratory disease COVID-19 and resulting in millions of deaths worldwide. As a coronavirus, SARS-CoV2 host interactions are dictated through the Spike proteins that encompass the virion. The Spike protein of SARS-CoV2, is a highly glycosylated trimer that interacts with the ACE2 receptor on host cells via the receptor binding domain (RBD) to facilitate viral entry. As a key player in viral infection, the Spike trimer, and the RBD, have become the target for a majority of approved therapeutics and vaccines used to treat or prevent SARS-CoV2. In this proposal, the PI uses a novel antiviral lectin, BOA, which he has demonstrated that BOA binds glycans on the spike protein, and inhibits SARS-CoV2 viral entry. To understand how BOA inhibits viral entry, during the K99 phase of the award, the PI will determine the mechanism by which BOA inhibits in SARS-CoV2 viral infection using a combination of viral inhibition assays, biophysical assays, and electron microscopy. Subsequently the PI will test the ability of BOA to inhibit emerging SARS-CoV2 variants of concern that have accumulated mutations to various regions of the spike protein that facilitate immune escape. Expanding upon these findings during the independent R00 phase of this award, the PI will use skills developed during the K99 phase to establish his own independent research group, where they will test the ability of the BOA lectin to inhibit viral entry of Beta- Coronaviruses known to infect humans. Successful completion of these aims could provide a bona fide broad spectrum coronavirus inhibitor to be further developed as a therapeutic or diagnostic for the next coronavirus that emerges. The proposed research, will provide the PI with new and exciting training in virology as well as electron microscopy which he intends to pass on to his future trainees. The proposed work will be completed at The University of Pittsburgh, where the Department of Structural Biology and Center for Vaccine Research will provide unmatched access to resources, instrumentation, and experts in the field. The PI has assembled an exciting mentorship team of virologists and biophysicists who he will meet with monthly to receive advice, discuss results, designed new experiments, and prepare for transitioning into an independent career. To aide in his career development, the university offers numerous workshops to develop skills such as grant writing and mentorship. The PI will also attend conferences to give presentations and hone his science communications skills. In Summary, the proposed training and career development plans will prepare the PI to lead his own independent research group and become a leader in his field.