# Structure-Function Analysis of Human and Bat Coronavirus Spike Proteins

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2024 · $234,000

## Abstract

Project Summary/Abstract
The COVID-19 pandemic has affected over 690 million people worldwide and caused 6.9 million deaths.
Although the recent variants are less infectious and cause lower mortality than earlier ones, diagnosed active
cases are as high as 20 million worldwide. SARS-CoV-2 spike protein is continuously accumulating mutations.
Our earlier published studies on its receptor-binding domain (RBD) showed that increased receptor binding
and escape from neutralizing antibodies direct the natural selection of mutations. However, mutations have
also been found in other regions of the spike protein, and the role of these non-RBD mutations is not well
understood. Computational models propose a long-range allosteric communication between different parts of
the spike protein. During this 2-year proposal period, we will design experiments to test the role of long-range
communication by probing the effect of distant mutations on RBD binding to ACE2 and to neutralizing
antibodies (Aim 1). Spike protein is a trimer and exists in multiple conformations with individual RBDs either
accessible or inaccessible to ACE2 and antibodies. We will probe the relative populations of the four
conformational states of the spike protein and the effect of mutations. In addition to SARS-CoV-2 emerged in
2019, two other coronaviruses (CoVs) have caused severe disease: SARS-CoV emerged in 2003 and MERS-
CoV in 2012. Though based on only three data points, the data suggests another COVID outbreak might be
imminent within the next ten years. Human coronaviruses (CoVs) are widely considered to have originated
from bats, and hence, multiple efforts worldwide have been focused on identifying bat CoVs capable of
infecting humans. So far, about 700 bat CoVs with unique spike proteins have been identified, and it is crucial
to determine which receptor pathways they might use to infect humans in order to develop effective therapies.
To begin with, we will examine which of these bat CoV spike proteins might use the ACE2 (SARS-CoV/SARS-
CoV-2) and DPP4 (MERS-CoV) pathways by combining bioinformatic sequence analysis and determining the
relative binding affinities (Aim 2). These assays will be further applied to determine which other receptor
pathways bat CoVs might use to infect the human respiratory system. The molecular knowledge gained during
this proposal will help us in predicting the evolution of the current SARS-CoV-2 virus and any future COVID
outbreaks, which will finally lead to developing effective therapeutics that can neutralize multiple CoVs.

## Key facts

- **NIH application ID:** 10871534
- **Project number:** 1R21AI183195-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Krishna M.G. Mallela
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $234,000
- **Award type:** 1
- **Project period:** 2024-06-12 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871534

## Citation

> US National Institutes of Health, RePORTER application 10871534, Structure-Function Analysis of Human and Bat Coronavirus Spike Proteins (1R21AI183195-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10871534. Licensed CC0.

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