Solid-phase synthesis of sterically hindered peptides via ribosome-mimicking molecular reactors.

RMMR-SPPS enables efficient solid-phase synthesis of peptides containing N-methylated and/or α,α-disubstituted amino acids, achieving crude purities up to 98% with improved yields.

• Why it matters: Sterically hindered peptide sequences are difficult to make by standard SPPS, limiting access to drug-like macrocyclic candidates with better stability and permeability.
• What they did: The protocol details step-by-step RMMR-SPPS setup, including making Oxyma-C as an activating unit precursor, preparing RMMR resin, and running the method in manual and automated synthesizer formats.
• The result: Using this ribosome-mimicking molecular reactor strategy, these difficult peptides are synthesized efficiently with crude purities up to 98%, supporting broader adoption for orally bioavailable or intracellularly targeted macrocyclic drug discovery.

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