Selective binders of a cotranslational folding intermediate

Cyclic peptides identified by mRNA display bind a nascent β-galactosidase intermediate with low-nanomolar affinity, while showing no detectable binding to the fully folded protein or ribosomes making other sequences.

• Why it matters: Drug discovery usually targets mature proteins, but whether transient cotranslational intermediates expose druggable pockets was unclear.
• What they did: Using mRNA display, the team selected cyclic peptides that recognize a nascent polypeptide during ribosome synthesis, then mapped selectivity with hydrogen/deuterium exchange–mass spectrometry and cryogenic electron microscopy.
• The result: The nascent chain forms an α-helix against the ribosome surface during ongoing translation, creating a cryptic pocket with ribosomal proteins uL23 and uL29 that the peptides exploit, enabling proof-of-concept for targeting biogenesis intermediates.

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