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Protein Science (2006), 15:14-27. Published by Cold Spring Harbor Laboratory Press. Copyright © 2006 The Protein Society
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REVIEW

A new generation of protein display scaffolds for molecular recognition

Ralf J. Hosse1, Achim Rothe2 and Barbara E. Power1,2

1 Preventative Health National Research Flagship and 2 CSIRO Molecular and Health Technologies, Parkville, Victoria 3052, Australia

Engineered antibodies and their fragments are invaluable tools for a vast range of biotechnological and pharmaceutical applications. However, they are facing increasing competition from a new generation of protein display scaffolds, specifically selected for binding virtually any target. Some of them have already entered clinical trials. Most of these nonimmunoglobulin proteins are involved in natural binding events and have amazingly diverse origins, frameworks, and functions, including even intrinsic enzyme activity. In many respects, they are superior over antibody-derived affinity molecules and offer an ever-extending arsenal of tools for, e.g., affinity purification, protein microarray technology, bioimaging, enzyme inhibition, and potential drug delivery. As excellent supporting frameworks for the presentation of polypeptide libraries, they can be subjected to powerful in vitro or in vivo selection and evolution strategies, enabling the isolation of high-affinity binding reagents. This article reviews the generation of these novel binding reagents, describing validated and advanced alternative scaffolds as well as the most recent nonimmunoglobulin libraries. Characteristics of these protein scaffolds in terms of structural stability, tolerance to multiple substitutions, ease of expression, and subsequent applications as specific targeting molecules are discussed. Furthermore, this review shows the close linkage between these novel protein tools and the constantly developing display, selection, and evolution strategies using phage display, ribosome display, mRNA display, cell surface display, or IVC (in vitro compartmentalization). Here, we predict the important role of these novel binding reagents as a toolkit for biotechnological and biomedical applications.

Keywords: protein display scaffolds; peptide libraries; nonimmunoglobulin frameworks; high affinity reagents; protein interactions; binding surface

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051817606.

Reprint requests to: Barbara E. Power, CSIROMolecular and Health Technologies, Protein Design for Diagnostics, 343 Royal Parade, Parkville, Victoria 3052, Australia; e-mail: barbara.power{at}csiro.au; fax: +61-3-9662-7314.


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