title: Rational design of aggregation-resistant bioactive peptides: reengineering human calcitonin.
abstract: A high propensity to aggregate into intractable deposits is a common problem limiting the production and use of many peptides and proteins in a wide range of biotechnological and pharmaceutical applications. Many therapeutic polypeptides are frequently abandoned at an early stage in their development because of problems with stability and aggregation. It has been shown recently that parameters describing the physicochemical properties of polypeptides can be used as predictors of protein aggregation. Here we demonstrate that these and similar tools can be applied to the rational redesign of bioactive molecules with a significantly reduced aggregation propensity without loss of physiological activity. This strategy has been exemplified by designing variants of the hormone calcitonin that show a significantly reduced aggregation propensity, yet maintain, or even increase, their potency when compared to the current therapeutic forms. The results suggest that this approach could be used successfully to enhance the solubility and efficacy of a wide range of other peptide and protein therapeutics.
authors: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors: Susan B
authors: SB
authors: Fowler
authors: Stephen
authors: S
authors: Poon
authors: Roman
authors: R
authors: Muff
authors: Fabrizio
authors: F
authors: Chiti
authors: Christopher M
authors: CM
authors: Dobson
authors: Jesús
authors: J
authors: Zurdo
mesh_terms: D052160:Benzothiazoles; D001702:Biopharmaceutics / Q000379:methods*; D002116:Calcitonin / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008854:Microscopy, Electron; D011485:Protein Binding; D015202:Protein Engineering / Q000379:methods*; D012995:Solubility; D013844:Thiazoles / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D013844:Thiazoles; C009462:thioflavin T; D002116:Calcitonin; D000242:Cyclic AMP