title: Encoded Silicon-Chip-Based Platform for Combinatorial Synthesis and Screening.
abstract: Solid-supported chemical libraries have proven useful for the rapid and cost-effective discovery of bioactive compounds. However, traditional on-bead screening involves time-intensive chemical characterization of hit compounds and high false positive rates. Herein, we report a new platform for encoded chemical synthesis and solid-supported screening using p-Chips, microsized silicon microtransponders capable of storing and emitting unique numerical identifiers (IDs). By encoding the structures of library members using p-Chip IDs, we can track compound identities throughout both split-and-pool synthesis and protein binding assays without destructive cleavage. Thanks to the numerical IDs, our p-Chip platform can provide binding constants for library members simply by stripping and reprobing with different protein concentrations, unlike traditional on-bead assays. To showcase these features, we synthesized a library of 108 hemagglutinin (HA) peptide variants using split-and-pool approach, and measured EC50s for each variant directly on p-Chips. On-chip EC50s obtained from these studies showed excellent correlation (80%) with those obtained using traditional ELISA methods. Our screen also yielded a false positive rate of 14%, markedly superior to that reported for conventional bead-based binding studies (66-96%).1-9 On the basis of these results, we believe the p-Chip platform has the potential to improve the effectiveness of solid-supported high-throughput screening by a significant margin.
authors.affiliation: Department of Chemistry, Yale University , 225 Prospect Street, New Haven, Connecticut 06511, United States.
authors.forename: Julian
authors.initials: J
authors.lastname: Vastl
authors.affiliation: Department of Chemistry, Yale University , 225 Prospect Street, New Haven, Connecticut 06511, United States.
authors.forename: Tina
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Yale University , 225 Prospect Street, New Haven, Connecticut 06511, United States.
authors.forename: Thi B
authors.initials: TB
authors.lastname: Trinh
authors.affiliation: Department of Chemistry, Yale University , 225 Prospect Street, New Haven, Connecticut 06511, United States.
authors.forename: David A
authors.identifier: 0000-0002-1102-8012
authors.initials: DA
authors.lastname: Spiegel
mesh_terms: D019943:Amino Acid Substitution; D000906:Antibodies / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D006388:Hemagglutinins / Q000737:chemistry* / Q000276:immunology; D057166:High-Throughput Screening Assays / Q000379:methods; D008689:Methacrylates / Q000737:chemistry; D019151:Peptide Library; D010455:Peptides / Q000032:analysis*; D011092:Polyethylene Glycols / Q000737:chemistry; D011485:Protein Binding; D012825:Silicon / Q000737:chemistry*; D013499:Surface Properties; D013816:Thermodynamics
chemical_list: D000906:Antibodies; D006388:Hemagglutinins; D008689:Methacrylates; D019151:Peptide Library; D010455:Peptides; C524499:polyethylene glycol methacrylate; D011092:Polyethylene Glycols; D012825:Silicon
keywords: combinatorial chemistry; peptide library; radiofrequency identification (RFID); silicon chips; split-and-pool synthesis