ArticleNature communications2022
A topological refactoring design strategy yields highly stable granulopoietic proteins.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed, 15 citations in OpenAlex.
- Tuning of G-CSFR signaling by de novo-designed agonists.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- A Complementarity-Based Approach to De Novo Binder Design.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Article
- A strategy to design protein-based antagonists against type I cytokine receptors.PLoS biology · 2024Article
- The Damietta Server: a comprehensive protein design toolkit.Nucleic acids research · 2024Article
- Differential transcriptional control of hematopoiesis in congenital and cyclic neutropenia patients harboringHaematologica · 2024Article
- The design of functional proteins using tensorized energy calculations.Cell reports methods · 2023Article
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Authors and funding
17 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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