# Biophysical characterization of SARS-CoV-2 spike protein - receptor interactions

> **NIH NIH R21** · LEHIGH UNIVERSITY · 2022 · $226,313

## Abstract

PROJECT SUMMARY/ABSTRACT
The current pandemic of Coronavirus Disease-2019 (COVID-19) has had devastating impacts across the world.
In order to enter human host cells, SARS-CoV-2, the virus causing COVID-19, uses its surface spike (S) protein
to attach to host cell surface receptors. Besides the best-known receptor, ACE2, a number of cell surface proteins,
including CD147, neuropilin-1 (NRP1) and DC-SIGN/L-SIGN, have been reported to bind to S protein and
mediate SARS-CoV-2 entry. Consistently, our preliminary studies using single-molecule force spectroscopy
show that CD147, NRP1 and L-SIGN can bind to the SARS-CoV-2 S protein with comparable affinities to those
of ACE2. Therefore, the possible multiple receptor utilization could, at least partially, explain the broad tissue
tropism and systemic complications of SARS-CoV-2 infection. However, it remains puzzling how the S protein
can bind to these structurally diverse molecules with high affinity. In addition, our all-atom structural modeling
data shows that most of the S protein surface is covered by glycans, and only when the S protein’s receptor
binding domain (RBD) is in the “up position” can it bind to a receptor without glycan interference. Therefore, we
hypothesize that limited regions on the S protein that are not covered by glycans, including the RBD in up position,
as well as the S1/S2 junctional region, may be responsible for binding all the receptors. In the proposed work,
we will systematically test the hypothesis using combined approaches of single-virus force spectroscopy, all-
atom molecular modeling and simulation and pseudovirus internalization/entry assays. Moreover, since SARS-
CoV-2 has two entry routes (direct viral-host membrane fusion or endocytic/macropinocytic internalization
followed by endosomal entry), the exact entry pathways that these receptors mediate are not yet clear. The
proposed research will determine whether every individual interaction is more prone to mediate direct viral-host
membrane fusion or viral endocytic/macropinocytic internalization. Two specific aims will be pursued: 1) to
characterize S protein interactions with host cell membrane receptors and 2) to determine the structural basis of
S protein’s broad receptor recognition. The study will elucidate the structural and biophysical mechanisms behind
S protein’s receptor recognition and utilization. Successful completion of this work will allow us to identify new
targets for antiviral therapies to treat the systemic complications of COVID-19.

## Key facts

- **NIH application ID:** 10445350
- **Project number:** 5R21AI163708-02
- **Recipient organization:** LEHIGH UNIVERSITY
- **Principal Investigator:** Wonpil Im
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $226,313
- **Award type:** 5
- **Project period:** 2021-07-06 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445350

## Citation

> US National Institutes of Health, RePORTER application 10445350, Biophysical characterization of SARS-CoV-2 spike protein - receptor interactions (5R21AI163708-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10445350. Licensed CC0.

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