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Generating a mirror-image monobody targeting MCP-1 via TRAP display and chemical protein synthesis

Author

Listed:
  • Gosuke Hayashi

    (Nagoya University)

  • Toshinori Naito

    (Nagoya University)

  • Sayaka Miura

    (Nagoya University)

  • Naoya Iwamoto

    (Kyoto University)

  • Yusuke Usui

    (Kyoto University)

  • Mika Bando-Shimizu

    (Kyoto University)

  • Sae Suzuki

    (Nagoya University)

  • Katsuaki Higashi

    (Kyoto University)

  • Motohiro Nonaka

    (Kyoto University)

  • Shinya Oishi

    (Kyoto University
    Kyoto Pharmaceutical University)

  • Hiroshi Murakami

    (Nagoya University
    Nagoya University
    Nagoya University)

Abstract

Biologically produced protein drugs are generally susceptible to degradation by proteases and often exhibit immunogenicity. To address this issue, mirror-image peptide/protein binders consisting of D-amino acids have been developed so far through the mirror-image phage display technique. Here, we develop a mirror-image protein binder derived from a monobody, one of the promising protein scaffolds, utilizing two notable technologies: chemical protein synthesis and TRAP display, an improved version of mRNA display. A sequential workflow of initial screening followed by affinity maturation, facilitated by TRAP display, generates an L-monobody with high affinity (KD = 1.3 nM) against monocyte chemoattractant protein-1 (MCP-1) D-enantiomer. The chemically synthesized D-monobody demonstrates strong and specific binding to L-MCP-1 and exhibits pharmaceutically favorable properties such as proteolytic resistance, minimal immune response, and a potent inhibitory effect on MCP-1-induced cell migration. This study elevates the value of mirror-image peptide/protein binders as an alternative modality in drug discovery.

Suggested Citation

  • Gosuke Hayashi & Toshinori Naito & Sayaka Miura & Naoya Iwamoto & Yusuke Usui & Mika Bando-Shimizu & Sae Suzuki & Katsuaki Higashi & Motohiro Nonaka & Shinya Oishi & Hiroshi Murakami, 2024. "Generating a mirror-image monobody targeting MCP-1 via TRAP display and chemical protein synthesis," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54902-x
    DOI: 10.1038/s41467-024-54902-x
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    1. Nina Schmidt & Amit Kumar & Lukas Korf & Adrian Valentin Dinh-Fricke & Frank Abendroth & Akiko Koide & Uwe Linne & Magdalena Rakwalska-Bange & Shohei Koide & Lars-Oliver Essen & Olalla Vázquez & Olive, 2024. "Development of mirror-image monobodies targeting the oncogenic BCR::ABL1 kinase," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Alex J. Callahan & Satish Gandhesiri & Tara L. Travaline & Rahi M. Reja & Lia Lozano Salazar & Stephanie Hanna & Yen-Chun Lee & Kunhua Li & Olena S. Tokareva & Jean-Marie Swiecicki & Andrei Loas & Gre, 2024. "Mirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
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    1. Nina Schmidt & Amit Kumar & Lukas Korf & Adrian Valentin Dinh-Fricke & Frank Abendroth & Akiko Koide & Uwe Linne & Magdalena Rakwalska-Bange & Shohei Koide & Lars-Oliver Essen & Olalla Vázquez & Olive, 2024. "Development of mirror-image monobodies targeting the oncogenic BCR::ABL1 kinase," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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