A multiplex method for rapidly identifying viral protease inhibitors
Abstract With current treatments addressing only a fraction of pathogens and new viral threats constantly evolving, there is a critical need to expand our existing therapeutic arsenal. To speed the rate of discovery and better prepare against future threats, we establish a high-throughput platform c...
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| Format: | Article |
| Language: | English |
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Springer Nature
2025-01-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.1038/s44320-024-00082-1 |
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| author | Seo Jung Hong Samuel J Resnick Sho Iketani Ji Won Cha Benjamin Alexander Albert Christopher T Fazekas Ching-Wen Chang Hengrui Liu Shlomi Dagan Michael R Abagyan Pavla Fajtová Bruce Culbertson Brooklyn Brace Eswar R Reddem Farhad Forouhar J Fraser Glickman James M Balkovec Brent R Stockwell Lawrence Shapiro Anthony J O’Donoghue Yosef Sabo Joel S Freundlich David D Ho Alejandro Chavez |
| author_facet | Seo Jung Hong Samuel J Resnick Sho Iketani Ji Won Cha Benjamin Alexander Albert Christopher T Fazekas Ching-Wen Chang Hengrui Liu Shlomi Dagan Michael R Abagyan Pavla Fajtová Bruce Culbertson Brooklyn Brace Eswar R Reddem Farhad Forouhar J Fraser Glickman James M Balkovec Brent R Stockwell Lawrence Shapiro Anthony J O’Donoghue Yosef Sabo Joel S Freundlich David D Ho Alejandro Chavez |
| author_sort | Seo Jung Hong |
| collection | DOAJ |
| description | Abstract With current treatments addressing only a fraction of pathogens and new viral threats constantly evolving, there is a critical need to expand our existing therapeutic arsenal. To speed the rate of discovery and better prepare against future threats, we establish a high-throughput platform capable of screening compounds against 40 diverse viral proteases simultaneously. This multiplex approach is enabled by using cellular biosensors of viral protease activity combined with DNA-barcoding technology, as well as several design innovations that increase assay sensitivity and correct for plate-to-plate variation. Among >100,000 compound-target interactions explored within our initial screen, a series of broad-acting inhibitors against coronavirus proteases were uncovered and validated through orthogonal assays. A medicinal chemistry campaign was performed to improve one of the inhibitor’s potency while maintaining its broad activity. This work highlights the power of multiplex screening to efficiently explore chemical space at a fraction of the time and costs of previous approaches. |
| format | Article |
| id | doaj-art-38129d8148fe46c68a231287fa8453fd |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-38129d8148fe46c68a231287fa8453fd2025-02-09T13:00:48ZengSpringer NatureMolecular Systems Biology1744-42922025-01-0121215817210.1038/s44320-024-00082-1A multiplex method for rapidly identifying viral protease inhibitorsSeo Jung Hong0Samuel J Resnick1Sho Iketani2Ji Won Cha3Benjamin Alexander Albert4Christopher T Fazekas5Ching-Wen Chang6Hengrui Liu7Shlomi Dagan8Michael R Abagyan9Pavla Fajtová10Bruce Culbertson11Brooklyn Brace12Eswar R Reddem13Farhad Forouhar14J Fraser Glickman15James M Balkovec16Brent R Stockwell17Lawrence Shapiro18Anthony J O’Donoghue19Yosef Sabo20Joel S Freundlich21David D Ho22Alejandro Chavez23Department of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and SurgeonsDepartment of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and SurgeonsAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsDepartment of Pediatrics, University of California San DiegoDepartment of Pediatrics, University of California San DiegoDepartment of Pediatrics, University of California San DiegoDivision of Infectious Diseases, Department of Medicine, Columbia University Vagelos College of Physicians and SurgeonsDepartment of Biological Sciences, Department of Chemistry, and Department of Pathology and Cell Biology, Columbia UniversityFisher Drug Discovery Resource Center, The Rockefeller UniversitySkaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San DiegoMedical Scientist Training Program, Columbia University Irving Medical CenterDepartment of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and SurgeonsDepartment of Biochemistry and Molecular Biophysics, Columbia UniversityDepartment of Pathology and Cell Biology and Columbia University Digestive and Liver Disease Research Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical CenterFisher Drug Discovery Resource Center, The Rockefeller UniversityCenter for Discovery and Innovation, Hackensack Meridian HealthDepartment of Biological Sciences, Department of Chemistry, and Department of Pathology and Cell Biology, Columbia UniversityAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San DiegoAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsDepartment of Pharmacology, Physiology, and Neuroscience, Rutgers University – New Jersey Medical SchoolAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and SurgeonsDepartment of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and SurgeonsAbstract With current treatments addressing only a fraction of pathogens and new viral threats constantly evolving, there is a critical need to expand our existing therapeutic arsenal. To speed the rate of discovery and better prepare against future threats, we establish a high-throughput platform capable of screening compounds against 40 diverse viral proteases simultaneously. This multiplex approach is enabled by using cellular biosensors of viral protease activity combined with DNA-barcoding technology, as well as several design innovations that increase assay sensitivity and correct for plate-to-plate variation. Among >100,000 compound-target interactions explored within our initial screen, a series of broad-acting inhibitors against coronavirus proteases were uncovered and validated through orthogonal assays. A medicinal chemistry campaign was performed to improve one of the inhibitor’s potency while maintaining its broad activity. This work highlights the power of multiplex screening to efficiently explore chemical space at a fraction of the time and costs of previous approaches.https://doi.org/10.1038/s44320-024-00082-1AntiviralBiosensorsDrug ScreeningHigh-ThroughputMultiplex |
| spellingShingle | Seo Jung Hong Samuel J Resnick Sho Iketani Ji Won Cha Benjamin Alexander Albert Christopher T Fazekas Ching-Wen Chang Hengrui Liu Shlomi Dagan Michael R Abagyan Pavla Fajtová Bruce Culbertson Brooklyn Brace Eswar R Reddem Farhad Forouhar J Fraser Glickman James M Balkovec Brent R Stockwell Lawrence Shapiro Anthony J O’Donoghue Yosef Sabo Joel S Freundlich David D Ho Alejandro Chavez A multiplex method for rapidly identifying viral protease inhibitors Molecular Systems Biology Antiviral Biosensors Drug Screening High-Throughput Multiplex |
| title | A multiplex method for rapidly identifying viral protease inhibitors |
| title_full | A multiplex method for rapidly identifying viral protease inhibitors |
| title_fullStr | A multiplex method for rapidly identifying viral protease inhibitors |
| title_full_unstemmed | A multiplex method for rapidly identifying viral protease inhibitors |
| title_short | A multiplex method for rapidly identifying viral protease inhibitors |
| title_sort | multiplex method for rapidly identifying viral protease inhibitors |
| topic | Antiviral Biosensors Drug Screening High-Throughput Multiplex |
| url | https://doi.org/10.1038/s44320-024-00082-1 |
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