Phage Display with Multiple Non-Canonical Amino Acids Enables ncAA-Containing Peptide Library Screening for Drug Discovery
Oller-Salvia, B., Chin, J.W.
Angewandte Chemie International Edition 58, 10844 (2019)
Published in Angewandte Chemie International Edition in 2019, this paper demonstrated that phage display, one of the most widely used methods for discovering peptide binders, can incorporate multiple distinct non-canonical amino acids into the displayed peptide libraries.
Phage display works by expressing peptide libraries on the surface of bacteriophage particles, then selecting for phages that bind a target of interest. It is a proven drug discovery method responsible for identifying peptide and antibody leads across many therapeutic areas. However, conventional phage display is limited to the 20 canonical amino acids, meaning the chemical diversity of the displayed library is restricted to natural protein chemistry.
This paper showed that orthogonal ribosome-mediated genetic code expansion can be used to incorporate multiple distinct ncAAs into phage-displayed peptides. The displayed library therefore contains peptides with chemical functionalities that do not exist in natural biology: conjugation handles, non-natural side chains, backbone modifications, and other features that can improve target binding, metabolic stability, or other drug-like properties.
The connection to Constructive Bio's platform is the discovery-to-manufacturing pipeline. ncAA-containing peptide hits identified through phage display can be produced at scale through BioForge fermentation using the same genetic code expansion technology. The ncAAs are genetically encoded in both the discovery phase (phage display) and the manufacturing phase (fermentation), so the chemistry that makes a hit molecule active is preserved through scale-up without requiring a switch to solid-phase peptide synthesis.
This work links genetic code expansion to one of the pharmaceutical industry's established discovery workflows, providing a path from ncAA-enhanced screening libraries through to fermentation-based manufacturing of lead candidates.
Why it matters
Drug discovery requires screening large libraries to find peptide candidates. This work enables those libraries to include non-canonical amino acids from the outset, rather than adding them later through chemical modification. Combined with the tRNA display technology that Constructive Bio has exclusively licenced, this creates an end-to-end discovery-to-manufacturing pipeline for ncAA-containing peptide therapeutics.
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