A topological refactoring design strategy yields highly stable granulopoietic proteins

Julia Skokowa (), Birte Hernandez Alvarez, Murray Coles, Malte Ritter, Masoud Nasri, Jérémy Haaf, Narges Aghaallaei, Yun Xu, Perihan Mir, Ann-Christin Krahl, Katherine W. Rogers, Kateryna Maksymenko, Baubak Bajoghli, Karl Welte, Andrei N. Lupas, Patrick Müller and Mohammad ElGamacy ()
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Julia Skokowa: University Hospital Tübingen
Birte Hernandez Alvarez: Max Planck Institute for Biology
Murray Coles: Max Planck Institute for Biology
Malte Ritter: University Hospital Tübingen
Masoud Nasri: University Hospital Tübingen
Jérémy Haaf: University Hospital Tübingen
Narges Aghaallaei: University Hospital Tübingen
Yun Xu: University Hospital Tübingen
Perihan Mir: University Hospital Tübingen
Ann-Christin Krahl: University Hospital Tübingen
Katherine W. Rogers: Friedrich Miescher Laboratory of the Max Planck Society
Kateryna Maksymenko: Max Planck Institute for Biology
Baubak Bajoghli: University Hospital Tübingen
Karl Welte: University Hospital Tübingen
Andrei N. Lupas: Max Planck Institute for Biology
Patrick Müller: Friedrich Miescher Laboratory of the Max Planck Society
Mohammad ElGamacy: University Hospital Tübingen

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Protein therapeutics frequently face major challenges, including complicated production, instability, poor solubility, and aggregation. De novo protein design can readily address these challenges. Here, we demonstrate the utility of a topological refactoring strategy to design novel granulopoietic proteins starting from the granulocyte-colony stimulating factor (G-CSF) structure. We change a protein fold by rearranging the sequence and optimising it towards the new fold. Testing four designs, we obtain two that possess nanomolar activity, the most active of which is highly thermostable and protease-resistant, and matches its designed structure to atomic accuracy. While the designs possess starkly different sequence and structure from the native G-CSF, they show specific activity in differentiating primary human haematopoietic stem cells into mature neutrophils. The designs also show significant and specific activity in vivo. Our topological refactoring approach is largely independent of sequence or structural context, and is therefore applicable to a wide range of protein targets.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30157-2

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DOI: 10.1038/s41467-022-30157-2

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