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. 2025 May 16;28(6):112687.
doi: 10.1016/j.isci.2025.112687. eCollection 2025 Jun 20. A combinatorial and computational Tandem approach towards a universal therapeutics against ACE2-mediated coronavirus infections
Chia Yin Lee 1 , Ching-Wen Huang 1 , Louis De Falco Jr 2 , Rabiatul Adawiyah Minhat 1 , Aurélien Traversier 3 4 5 , Bei Wang 1 , Siti Nazihah Mohd Salleh 1 , Eve Zi Xian Ngoh 1 , Yuling Huang 6 , Jenna Kim 6 , Matthew Zirui Tay 6 , Manuel Rosa-Calatrava 3 4 5 , Andrés Pizzorno 3 4 , Roland G Huber 2 , Cheng-I Wang 1
Affiliations
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.
Keywords: Biochemistry; Biological sciences; Microbiology; Natural sciences; Virology.
. 2025 May 16;28(6):112687.
doi: 10.1016/j.isci.2025.112687. eCollection 2025 Jun 20. A combinatorial and computational Tandem approach towards a universal therapeutics against ACE2-mediated coronavirus infections
Chia Yin Lee 1 , Ching-Wen Huang 1 , Louis De Falco Jr 2 , Rabiatul Adawiyah Minhat 1 , Aurélien Traversier 3 4 5 , Bei Wang 1 , Siti Nazihah Mohd Salleh 1 , Eve Zi Xian Ngoh 1 , Yuling Huang 6 , Jenna Kim 6 , Matthew Zirui Tay 6 , Manuel Rosa-Calatrava 3 4 5 , Andrés Pizzorno 3 4 , Roland G Huber 2 , Cheng-I Wang 1
Affiliations
- PMID: 40520104
- PMCID: PMC12164199
- DOI: 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.
Keywords: Biochemistry; Biological sciences; Microbiology; Natural sciences; Virology.