ArticleProtein science : a publication of the Protein Society2002
Development of a cytokine analog with enhanced stability using computational ultrahigh throughput screening.
Article in Protein science : a publication of the Protein Society, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 56 citations in OpenAlex.
- Engineering the kinetic stability of a β-trefoil protein by tuning its topological complexity.Frontiers in molecular biosciences · 2023Article
- Instability Challenges and Stabilization Strategies of Pharmaceutical Proteins.Pharmaceutics · 2022Review
- A topological refactoring design strategy yields highly stable granulopoietic proteins.Nature communications · 2022Article
- Design of novel granulopoietic proteins by topological rescaffolding.PLoS biology · 2020Article
- Review: Engineering of thermostable enzymes for industrial applications.APL bioengineering · 2018Review
- Computational approaches for predicting mutant protein stability.Journal of computer-aided molecular design · 2016Review
- Improved drug-like properties of therapeutic proteins by directed evolution.Protein engineering, design & selection : PEDS · 2012Article
- Computational approaches for rational design of proteins with novel functionalities.Computational and structural biotechnology journal · 2012Review
- Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity.Molecular pharmacology · 2009Article
- Bioinformatic method for protein thermal stabilization by structural entropy optimization.Proceedings of the National Academy of Sciences of the United States of America · 2008Article
- Modulation of protein aggregation by polyethylene glycol conjugation: GCSF as a case study.Protein science : a publication of the Protein Society · 2006Article
- Rational design of intercellular adhesion molecule-1 (ICAM-1) variants for antagonizing integrin lymphocyte function-associated antigen-1-dependent adhesion.The Journal of biological chemistry · 2006Article
- Stabilizing peptide fusion for solving the stability and solubility problems of therapeutic proteins.Pharmaceutical research · 2005Article
- Computational thermostabilization of an enzyme.Science (New York, N.Y.) · 2005Article
- Characterizing biological products and assessing comparability following manufacturing changes.Nature biotechnology · 2004Article
- Combining computational and experimental screening for rapid optimization of protein properties.Proceedings of the National Academy of Sciences of the United States of America · 2002Article
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Granulocyte-colony stimulating factor (G-CSF) is used worldwide to prevent neutropenia caused by high-dose chemotherapy. It has limited stability, strict formulation and storage requirements, and because of poor oral absorption must be administered by injection (typically daily). Thus, there is significant interest in developing analogs with improved pharmacological properties. We used our ultrahigh throughput computational screening method to improve the physicochemical characteristics of G-CSF. Improving these properties can make a molecule more robust, enhance its shelf life, or make it more amenable to alternate delivery systems and formulations. It can also affect clinically important features such as pharmacokinetics. Residues in the buried core were selected for optimization to minimize changes to the surface, thereby maintaining the active site and limiting the designed protein's potential for antigenicity. Using a structure that was homology modeled from bovine G-CSF, core designs of 25-34 residues were completed, corresponding to 10(21)-10(28) sequences screened. The optimal sequence from each design was selected for biophysical characterization and experimental testing; each had 10-14 mutations. The designed proteins showed enhanced thermal stabilities of up to 13 degrees C, displayed five-to 10-fold improvements in shelf life, and were biologically active in cell proliferation assays and in a neutropenic mouse model. Pharmacokinetic studies in monkeys showed that subcutaneous injection of the designed analogs results in greater systemic exposure, probably attributable to improved absorption from the subcutaneous compartment. These results show that our computational method can be used to develop improved pharmaceuticals and illustrate its utility as a powerful protein design tool.
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