# Targeting early metastable intermediates of the SARS-CoV-2 spike for vaccine and therapeutics development

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $732,990

## Abstract

Targeting early metastable intermediates of the SARS-CoV-2 spike for vaccine and therapeutics development
The ongoing global pandemic of the novel SARS-CoV-2 presents an urgent need for
development of effective preventative and treatment therapies. The viral-host cell fusion (S) protein spike is a
prime target for such therapies owing to its critical role in the virus lifecycle. The S protein is divided into two
regions: the N-terminal S1 domain that caps the C-terminal S2 fusion domain. Binding to host receptor via the
Receptor Binding Domain (RBD) in S1 is followed by proteolytic cleavage of the spike by host proteases. This
leads dramatic conformational transitions resulting in S1 shedding and exposure of the fusion machinery in S2,
culminating in host-cell entry. Class I fusion proteins such as the CoV S protein that undergo large
conformational changes during the fusion process must, by necessity, be highly flexible and dynamic. Indeed,
cryo-EM structures of the SARS-CoV-2 spike reveal considerable flexibility and dynamics in the S1 domain,
especially around the RBD that exhibits two discrete conformational states – a “down” state that is shielded
from receptor binding, and an “up” state that is receptor-accessible. The overall goals of this study are to use
our robust, high-throughput computational and experimental pipeline to define the detailed trajectory of the
“down” to “up” transition of the SARS-CoV-2 S protein, identify early metastable intermediates in the fusion
pathway, and exploit their structures and dynamics for identifying drug and vaccine candidates that target
SARS-CoV-2. A wealth of structural information on CoV spike proteins, including recently determined cryo-EM
structures of the SARS-CoV-2 spike, provides a rich source of detailed data from which to begin precise
examination of macromolecular transitions underlying triggering of this fusion machine. The scientific premise
of this study is that understanding the structural dynamics and early transition kinetics of mobile regions of the
SARS-CoV-2 spike will allow optimal control of vaccine and drug responses, and facilitate the development of
novel antiviral drugs and protective vaccines. At the culmination of this study, we expect to have determined
structures of multiple “down”, “up”, and intermediate states of the SARS-CoV-2 S protein. Together, these
studies will provide important atomically detailed structural and mechanistic information for exploitation in
vaccine and therapeutics design.

## Key facts

- **NIH application ID:** 10132065
- **Project number:** 3R01AI145687-02S1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Priyamvada Acharya
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $732,990
- **Award type:** 3
- **Project period:** 2020-05-21 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132065

## Citation

> US National Institutes of Health, RePORTER application 10132065, Targeting early metastable intermediates of the SARS-CoV-2 spike for vaccine and therapeutics development (3R01AI145687-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10132065. Licensed CC0.

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