A combinatorial and computational Tandem approach towards a universal therapeutics against ACE2-mediated coronavirus infections

A combinatorial and computational Tandem approach towards a universal therapeutics against ACE2-mediated coronavirus infections

iScience

10.1016/j.isci.2025.112687

https://doi.org/10.1016/j.isci.2025.112687

Chia Yin Lee, Ching-Wen Huang, Louis De Falco, Rabiatul Adawiyah Minhat, Aurélien Traversier, Bei Wang, Siti Nazihah Mohd Salleh, Eve Zi Xian Ngoh, Yuling Huang, Jenna Kim, Matthew Zirui Tay, Manuel Rosa-Calatrava, Andrés Pizzorno, Roland G. Huber, Cheng-I Wang

16 May 2025

Lee, C. Y., Huang, C.-W., De Falco, L., Minhat, R. A., Traversier, A., Wang, B., Mohd Salleh, S. N., Ngoh, E. Z. X., Huang, Y., Kim, J., Tay, M. Z., Rosa-Calatrava, M., Pizzorno, A., Huber, R. G., & Wang, C.-I. (2025). A combinatorial and computational Tandem approach towards a universal therapeutics against ACE2-mediated coronavirus infections. IScience, 28(6), 112687. https://doi.org/10.1016/j.isci.2025.112687

Angiotensin-converting enzyme 2 (ACE2) receptor plays a pivotal role in the infection of several coronaviruses, including SARS-CoV and SARS-CoV-2. We combined computational and experimental protein engineering approaches to develop ACE2-YHA, a soluble, high-affinity ACE2 decoy with pan-coronavirus preventive and therapeutic potential. Leveraging native human ACE2–SARS-CoV/SARS-CoV-2 receptor binding domain (RBD) complex homology models, we employed in silico site-saturation mutagenesis to predict key ACE2-RBD interacting residues. Subsequent generation of ACE2 mutants and high-throughput screening identified specific ACE2 residue substitutions that enhanced binding to both SARS-CoV and SARS-CoV-2 RBDs. The triple mutant ACE2-YHA demonstrated significantly enhanced binding affinity to SARS-CoV, SARS-CoV-2, and bat SARSr-CoVs’ RBDs. It effectively neutralized SARS-CoV and numerous SARS-CoV-2 variants with picomolar IC50s in pseudotyped virus assays. Notably, ACE2-YHA displayed potent neutralization against major variants of concern, including Delta and Omicron, in human airway epithelia, positioning it as a promising universal decoy for current and future ACE2-binding coronavirus outbreaks.

Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)

This research / project is supported by the A*STAR Biomedical Research Council (BMRC) - COVID-19 research fund
Grant Reference no. : H20/04/g1/005

This research / project is supported by the Ministry of Health (MOH) - Programme for Research in Epidemic Preparedness and REsponse (PREPARE)
Grant Reference no. : PREPARE-OC-VT-2022-001

For the publisher's version, please refer here: https://doi.org/10.1016/j.isci.2025.112687

https://oar.a-star.edu.sg/communities-collections/articles/21890

2589-0042

Singapore Immunology Network