Encoded Silicon-Chip-Based Platform for Combinatorial Synthesis and Screening

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%).− 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.