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

Summary: 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-coro...

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Main Authors: Chia Yin Lee, Ching-Wen Huang, Louis De Falco, Jr., 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
Format: Article
Language:English
Published: Elsevier 2025-06-01
Series:iScience
Subjects:
Natural sciences
Biological sciences
Biochemistry
Microbiology
Virology
Online Access:http://www.sciencedirect.com/science/article/pii/S2589004225009484
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Summary:Summary: 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.
ISSN:2589-0042

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