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Updated: Jan 10, 2026
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Protein Engineering by Yeast Surface Display
Published on: November 29, 2024
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Pharmacophore-driven antibody discovery on the yeast surface
Manjie Huang1, Sean J Williams1, Vikas D Trivedi1
1Chemical and Biological Engineering Department, Tufts University, Medford, Massachusetts 02155, United States.
Biorxiv : the Preprint Server for Biology
|November 24, 2025
Summary
We developed a novel method for discovering protein-small molecule hybrids using pharmacophore-driven antibody discovery. This high-throughput approach successfully generated potent hybrid molecules with therapeutic potential.
Area of Science:
- Biotechnology
- Chemical Biology
- Immunology
Background:
- Protein-small molecule hybrids combine small molecule inhibition with protein specificity.
- Discovering synergistic conjugates presents a significant engineering challenge.
Purpose of the Study:
- To describe pharmacophore-driven antibody discovery as a high-throughput method for hybrid discovery.
- To explore the utility of introducing pharmacophores into antibody libraries.
Main Methods:
- Utilized a yeast display antibody library with reactive noncanonical amino acids (ncAAs).
- Diversified the library by conjugating it to four sulfonamide pharmacophores.
- Performed yeast display binding screens against bovine carbonic anhydrase (bCA).
Main Results:
- Billion-member hybrid collections yielded diverse hybrids with double-digit nanomolar binding affinities.
- Screening outcomes were strongly pharmacophore-dependent, influencing enrichment diversity.
- Isolated clones demonstrated tolerance to alternative pharmacophores but preferred the screening pharmacophore.
Conclusions:
- Pharmacophore-driven antibody discovery is a viable high-throughput approach for hybrid discovery.
- Screening outcomes are significantly influenced by the choice of pharmacophore.
- These hybrids show promise as research tools and potential therapeutic leads.
