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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| Language: | English |
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Elsevier
2025-06-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225009484 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Chia Yin Lee |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8adbfeb970334e7599f886cb991f098e |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-8adbfeb970334e7599f886cb991f098e2025-08-20T03:55:22ZengElsevieriScience2589-00422025-06-0128611268710.1016/j.isci.2025.112687A combinatorial and computational Tandem approach towards a universal therapeutics against ACE2-mediated coronavirus infectionsChia Yin Lee0Ching-Wen Huang1Louis De Falco, Jr.2Rabiatul Adawiyah Minhat3Aurélien Traversier4Bei Wang5Siti Nazihah Mohd Salleh6Eve Zi Xian Ngoh7Yuling Huang8Jenna Kim9Matthew Zirui Tay10Manuel Rosa-Calatrava11Andrés Pizzorno12Roland G. Huber13Cheng-I Wang14Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), 8A Biomedical Grove, Immunos #03-06, Singapore 138648, Republic of SingaporeSingapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), 8A Biomedical Grove, Immunos #03-06, Singapore 138648, Republic of SingaporeBioinformatics Institute (BII), Agency for Science, Technology and Research (A∗STAR), 30 Biopolis Street, Matrix #07-01, Singapore 138671, Republic of SingaporeSingapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), 8A Biomedical Grove, Immunos #03-06, Singapore 138648, Republic of SingaporeCIRI, Centre International de Recherche en Infectiologie, Team VirPath, INSERM U1111, CNRS UMR 5308, ENS de Lyon, Université Claude Bernard Lyon 1, Lyon, France; International Research Laboratory RESPIVIR France - Canada, Centre de Recherche en Infectiologie, Faculté de Médecine RTH Laennec, 69008 Lyon, France, Université Claude Bernard Lyon 1, Université de Lyon, INSERM, CNRS, ENS de Lyon, France, Centre Hospitalier Universitaire de Québec - Université Laval, Québec, QC G1V 4G2, Canada; VirNext, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, 69008 Lyon, FranceSingapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), 8A Biomedical Grove, Immunos #03-06, Singapore 138648, Republic of SingaporeSingapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), 8A Biomedical Grove, Immunos #03-06, Singapore 138648, Republic of SingaporeSingapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), 8A Biomedical Grove, Immunos #03-06, Singapore 138648, Republic of SingaporeInfectious Diseases Labs (ID Labs), Agency for Science, Technology and Research (A∗STAR), 8A Biomedical Grove, Immunos #05-13, Singapore 138648, Republic of SingaporeInfectious Diseases Labs (ID Labs), Agency for Science, Technology and Research (A∗STAR), 8A Biomedical Grove, Immunos #05-13, Singapore 138648, Republic of SingaporeInfectious Diseases Labs (ID Labs), Agency for Science, Technology and Research (A∗STAR), 8A Biomedical Grove, Immunos #05-13, Singapore 138648, Republic of SingaporeCIRI, Centre International de Recherche en Infectiologie, Team VirPath, INSERM U1111, CNRS UMR 5308, ENS de Lyon, Université Claude Bernard Lyon 1, Lyon, France; International Research Laboratory RESPIVIR France - Canada, Centre de Recherche en Infectiologie, Faculté de Médecine RTH Laennec, 69008 Lyon, France, Université Claude Bernard Lyon 1, Université de Lyon, INSERM, CNRS, ENS de Lyon, France, Centre Hospitalier Universitaire de Québec - Université Laval, Québec, QC G1V 4G2, Canada; VirNext, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, 69008 Lyon, FranceCIRI, Centre International de Recherche en Infectiologie, Team VirPath, INSERM U1111, CNRS UMR 5308, ENS de Lyon, Université Claude Bernard Lyon 1, Lyon, France; International Research Laboratory RESPIVIR France - Canada, Centre de Recherche en Infectiologie, Faculté de Médecine RTH Laennec, 69008 Lyon, France, Université Claude Bernard Lyon 1, Université de Lyon, INSERM, CNRS, ENS de Lyon, France, Centre Hospitalier Universitaire de Québec - Université Laval, Québec, QC G1V 4G2, CanadaBioinformatics Institute (BII), Agency for Science, Technology and Research (A∗STAR), 30 Biopolis Street, Matrix #07-01, Singapore 138671, Republic of SingaporeSingapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), 8A Biomedical Grove, Immunos #03-06, Singapore 138648, Republic of Singapore; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004225009484Natural sciencesBiological sciencesBiochemistryMicrobiologyVirology |
| spellingShingle | 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 A combinatorial and computational Tandem approach towards a universal therapeutics against ACE2-mediated coronavirus infections iScience Natural sciences Biological sciences Biochemistry Microbiology Virology |
| title | A combinatorial and computational Tandem approach towards a universal therapeutics against ACE2-mediated coronavirus infections |
| title_full | A combinatorial and computational Tandem approach towards a universal therapeutics against ACE2-mediated coronavirus infections |
| title_fullStr | A combinatorial and computational Tandem approach towards a universal therapeutics against ACE2-mediated coronavirus infections |
| title_full_unstemmed | A combinatorial and computational Tandem approach towards a universal therapeutics against ACE2-mediated coronavirus infections |
| title_short | A combinatorial and computational Tandem approach towards a universal therapeutics against ACE2-mediated coronavirus infections |
| title_sort | combinatorial and computational tandem approach towards a universal therapeutics against ace2 mediated coronavirus infections |
| topic | Natural sciences Biological sciences Biochemistry Microbiology Virology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225009484 |
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