Skip to main content
placeholder image

Rational design of aggregation-resistant bioactive peptides: reengineering human calcitonin.

Journal Article


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.

UOW Authors


  •   Poon, Stephen (external author)

Publication Date


  • 2005

Citation


  • Fowler, S. B., Poon, S., Muff, R., Chiti, F., Dobson, C. M., & Zurdo, J. (2005). Rational design of aggregation-resistant bioactive peptides: reengineering human calcitonin.. Proceedings of the National Academy of Sciences of the United States of America, 102(29), 10105-10110. doi:10.1073/pnas.0501215102

Web Of Science Accession Number


Start Page


  • 10105

End Page


  • 10110

Volume


  • 102

Issue


  • 29

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.

UOW Authors


  •   Poon, Stephen (external author)

Publication Date


  • 2005

Citation


  • Fowler, S. B., Poon, S., Muff, R., Chiti, F., Dobson, C. M., & Zurdo, J. (2005). Rational design of aggregation-resistant bioactive peptides: reengineering human calcitonin.. Proceedings of the National Academy of Sciences of the United States of America, 102(29), 10105-10110. doi:10.1073/pnas.0501215102

Web Of Science Accession Number


Start Page


  • 10105

End Page


  • 10110

Volume


  • 102

Issue


  • 29