# Large-scale compatibility assessments between ACE2 proteins and diverse sarbecovirus spikes

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $201,250

## Abstract

PROJECT SUMMARY
 Viral spillover from animal reservoirs into humans can decimate public health systems and cripple the
world economy, as evident with the current SARS-CoV-2 pandemic. Continued wildlife habitat destruction,
human expansion, and routine global travel keep increasing the likelihood that another viral pandemic will
occur again within the next few decades. Beta coronaviruses are an incredibly diverse family of viruses
observed across Asia, Europe, and Africa, that have proven capable of zoonotic spillover into humans as they
have caused multiple worldwide outbreaks over the last two decades. We still lack the fundamental
understanding of the molecular and genetic factors that dictate the molecular compatibilities that determine
which beta coronaviruses are most likely to jump into humans in the future.
 The ability of SARS-like beta coronaviruses to utilize ACE2 as a receptor for cell entry is a major factor
determining the extent of coronavirus tropism across species or within the tissues of an organism. While
SARS-CoV-2 has been heavily studied, almost nothing is known about most other members of this virus
family. Traditional studies can only test a handful of conditions at a time, incompletely sampling the vast range
of relevant experimental conditions, particularly for the hundreds of uncharacterized beta coronaviruses. Large-
scale, minimally-biased, cell-based entry assays are needed to model how these factors converge to dictate
the probability of infection.
 We will pair new methods in cell engineering and synthetic biology with DNA-sequencing enabled
multiplex genetic assays to perform a series of large-scale infection assays revealing the factors determining
susceptibility to beta coronavirus entry. These large-scale experiments will reveal how ACE2 sequence and
cell surface density impact the efficiency of virus entry. By testing a library of receptor binding domain
sequences identified from ecological surveillance of bat coronaviruses, we will identify which viruses possess
sufficient affinity to human ACE2 to potentiate cross-species transmission, and create a catalog describing all
of the different ways these viruses have evolved their sequences to engage ACE2. By modeling the
relationship between spike and ACE2 protein sequence, expression level, and efficiency of cell entry, we will
identify potential animal reservoirs for SARS-CoV-2 and other SARS-like bat coronaviruses, and predict which
viruses have sufficient binding with human ACE2 to potentially spark the next pandemic.

## Key facts

- **NIH application ID:** 10874557
- **Project number:** 5R21AI178151-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Kenneth A Matreyek
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $201,250
- **Award type:** 5
- **Project period:** 2023-06-23 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874557

## Citation

> US National Institutes of Health, RePORTER application 10874557, Large-scale compatibility assessments between ACE2 proteins and diverse sarbecovirus spikes (5R21AI178151-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10874557. Licensed CC0.

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