Development of mirror-image monobodies targeting the oncogenic BCR::ABL1 kinase

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 () and Oliver Hantschel ()
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Nina Schmidt: Philipps University of Marburg
Amit Kumar: Philipps University of Marburg
Lukas Korf: Philipps University of Marburg
Adrian Valentin Dinh-Fricke: Philipps University of Marburg
Frank Abendroth: Philipps University of Marburg
Akiko Koide: New York University School of Medicine
Uwe Linne: Philipps University of Marburg
Magdalena Rakwalska-Bange: Philipps University of Marburg
Shohei Koide: New York University Langone Health
Lars-Oliver Essen: Philipps University of Marburg
Olalla Vázquez: Philipps University of Marburg
Oliver Hantschel: Philipps University of Marburg
Authors registered in the RePEc Author Service: Nina Smith

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Mirror-image proteins, composed of d-amino acids, are an attractive therapeutic modality, as they exhibit high metabolic stability and lack immunogenicity. Development of mirror-image binding proteins is achieved through chemical synthesis of d-target proteins, phage display library selection of l-binders and chemical synthesis of (mirror-image) d-binders that consequently bind the physiological l-targets. Monobodies are well-established synthetic (l-)binding proteins and their small size (~90 residues) and lack of endogenous cysteine residues make them particularly accessible to chemical synthesis. Here, we develop monobodies with nanomolar binding affinities against the d-SH2 domain of the leukemic tyrosine kinase BCR::ABL1. Two crystal structures of heterochiral monobody-SH2 complexes reveal targeting of the pY binding pocket by an unconventional binding mode. We then prepare potent d-monobodies by either ligating two chemically synthesized d-peptides or by self-assembly without ligation. Their proper folding and stability are determined and high-affinity binding to the l-target is shown. d-monobodies are protease-resistant, show long-term plasma stability, inhibit BCR::ABL1 kinase activity and bind BCR::ABL1 in cell lysates and permeabilized cells. Hence, we demonstrate that functional d-monobodies can be developed readily. Our work represents an important step towards possible future therapeutic use of d-monobodies when combined with emerging methods to enable cytoplasmic delivery of monobodies.

Date: 2024
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DOI: 10.1038/s41467-024-54901-y

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