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<p>The incorporation of <i>N</i>-methylated or α,α-disubstituted amino acids into peptides can markedly enhance their drug-like properties by improving proteolytic stability and membrane permeability. However, the solid-phase synthesis of such sterically hindered peptides remains a persistent challenge. Here we present a detailed protocol based on our recently developed ribosome-mimicking molecular reactor (RMMR) strategy, which substantially improves the synthetic efficiency of these difficult sequences via solid phase peptide synthesis (SPPS). This protocol provides a comprehensive, step-by-step procedure to facilitate a quick startup by the users, including the synthesis of Oxyma-C as the key activating unit precursor in the RMMR structure, the preparation of RMMR resin through modification of conventional SPPS resin and implementation of RMMR-SPPS in both manual and automated synthesizer formats. Peptides containing <i>N</i>-methylated and/or α,α-disubstituted amino acid(s) are synthesized efficiently using our strategy, with crude purities of up to 98% and respectable isolated yields, greatly surpassing existing methods. It is anticipated that this approach will facilitate broader adoption of RMMR-SPPS, addressing critical technical gaps and accelerating the discovery of orally bioavailable or intracellularly targeted macrocyclic peptide drug candidates.</p>

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

  • 期刊论文

  • 发表日期：

    2026年6月17日

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  • Siyuan Wei,
  • Xuchun Zhang,
  • Yishan Guo,
  • Fa Liu,
  • Zhu-Jun Yao

摘要

The incorporation of N-methylated or α,α-disubstituted amino acids into peptides can markedly enhance their drug-like properties by improving proteolytic stability and membrane permeability. However, the solid-phase synthesis of such sterically hindered peptides remains a persistent challenge. Here we present a detailed protocol based on our recently developed ribosome-mimicking molecular reactor (RMMR) strategy, which substantially improves the synthetic efficiency of these difficult sequences via solid phase peptide synthesis (SPPS). This protocol provides a comprehensive, step-by-step procedure to facilitate a quick startup by the users, including the synthesis of Oxyma-C as the key activating unit precursor in the RMMR structure, the preparation of RMMR resin through modification of conventional SPPS resin and implementation of RMMR-SPPS in both manual and automated synthesizer formats. Peptides containing N-methylated and/or α,α-disubstituted amino acid(s) are synthesized efficiently using our strategy, with crude purities of up to 98% and respectable isolated yields, greatly surpassing existing methods. It is anticipated that this approach will facilitate broader adoption of RMMR-SPPS, addressing critical technical gaps and accelerating the discovery of orally bioavailable or intracellularly targeted macrocyclic peptide drug candidates.