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

Gosuke Hayashi (), Toshinori Naito, Sayaka Miura, Naoya Iwamoto, Yusuke Usui, Mika Bando-Shimizu, Sae Suzuki, Katsuaki Higashi, Motohiro Nonaka (), Shinya Oishi () and Hiroshi Murakami ()
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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
Hiroshi Murakami: Nagoya University

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54902-x

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