Aggregation pathway of recombinant human keratinocyte growth factor and its stabilization

Recombinant human keratinocyte growth factor (rhKGF) is prone to aggregation at elevated temperatures. Its aggregation pathway is proposed to proceed initially with a conformational change which perhaps results from repulsion between positively charged residues in clusters forming heparin binding si...

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Bibliographic Details
Published in:Pharmaceutical research 1994-11, Vol.11 (11), p.1581-1587
Main Authors: BAO-LU CHEN, ARAKAWA, T, MORRIS, C. F, KENNEY, W. C, WELLS, C. M, PITT, C. G
Format: Article
Language:English
Subjects:
Anions
Biological and medical sciences
Buffers
Chemical Precipitation
Citrates - chemistry
Citric Acid
Drug Stability
Fibroblast Growth Factor 10
Fibroblast Growth Factor 7
Fibroblast Growth Factors
General pharmacology
Growth Substances - chemistry
Humans
Medical sciences
Pharmacology. Drug treatments
Physicochemical properties. Structure-activity relationships
Recombinant Proteins - chemistry
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Summary:Recombinant human keratinocyte growth factor (rhKGF) is prone to aggregation at elevated temperatures. Its aggregation pathway is proposed to proceed initially with a conformational change which perhaps results from repulsion between positively charged residues in clusters forming heparin binding sites. Unfolding of the protein leads to formation of large soluble aggregates. These soluble aggregates then form disulfide cross-linked precipitates. Finally these precipitates are converted to scrambled disulfides and/or non-disulfide cross-linked precipitates. Stabilizers such as heparin, sulfated polysaccharides, anionic polymers and citrate can greatly decrease the rate of aggregation of rhKGF at elevated temperatures. These molecules may all act by reducing charge repulsion on the protein thus stabilizing the native conformation. EDTA, on the other hand, is found to inhibit disulfide formation in aggregates and has only a moderate stabilizing effect on rhKGF.
ISSN:0724-8741
1573-904X
DOI:10.1023/A:1018905720139