Lasso-grafting of macrocyclic peptide pharmacophores yields multi-functional proteins

Emiko Mihara, Satoshi Watanabe, Nasir K. Bashiruddin, Nozomi Nakamura, Kyoko Matoba, Yumi Sano, Rumit Maini, Yizhen Yin, Katsuya Sakai, Takao Arimori, Kunio Matsumoto, Hiroaki Suga () and Junichi Takagi ()
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Emiko Mihara: Osaka University
Satoshi Watanabe: Osaka University
Nasir K. Bashiruddin: The University of Tokyo
Nozomi Nakamura: Osaka University
Kyoko Matoba: Osaka University
Yumi Sano: Osaka University
Rumit Maini: The University of Tokyo
Yizhen Yin: The University of Tokyo
Katsuya Sakai: Kanazawa University
Takao Arimori: Osaka University
Kunio Matsumoto: Kanazawa University
Hiroaki Suga: The University of Tokyo
Junichi Takagi: Osaka University

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Protein engineering has great potential for devising multifunctional recombinant proteins to serve as next-generation protein therapeutics, but it often requires drastic modifications of the parental protein scaffolds e.g., additional domains at the N/C-terminus or replacement of a domain by another. A discovery platform system, called RaPID (Random non-standard Peptides Integrated Discovery) system, has enabled rapid discovery of small de novo macrocyclic peptides that bind a target protein with high binding specificity and affinity. Capitalizing on the optimized binding properties of the RaPID-derived peptides, here we show that RaPID-derived pharmacophore sequences can be readily implanted into surface-exposed loops on recombinant proteins and maintain both the parental peptide binding function(s) and the host protein function. We refer to this protein engineering method as lasso-grafting and demonstrate that it can endow specific binding capacity toward various receptors into a diverse set of scaffolds that includes IgG, serum albumin, and even capsid proteins of adeno-associated virus, enabling us to rapidly formulate and produce bi-, tri-, and even tetra-specific binder molecules.

Date: 2021
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DOI: 10.1038/s41467-021-21875-0

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