Phage display screening for peptides that inhibit polyglutamine aggregation.
Proteins with expanded polyglutamine domains cause nine dominantly inherited, neurodegenerative diseases, including Huntington's disease. There are no therapies that inhibit disease onset or progression. To identify a novel therapeutic, we screened phage displayed peptide libraries for phage that bind preferentially to expanded polyglutamine repeats. We identified a peptide motif that inhibits polyglutamine aggregation in vitro and inhibits death in cellular and Drosophila models of the polyglutamine repeat diseases. In this chapter, we describe in detail how to screen a peptide phage display library and highlight results demonstrating the success of this approach. A similar experimental approach could be used for other diseases caused by conformational change in disease proteins, including prion, Alzheimer's, and Parkinson's diseases.
Kenan
Daniel J
DJ
Duke University Medical Center, Department of Medicine (Neurology) and Deane Laboratory, Durham, North Carolina, USA.
Strittmatter
Warren J
WJ
Burke
James R
JR
D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral; D017104:Bacteriophage M13 / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D036022:Capsid Proteins; D004268:DNA-Binding Proteins / Q000235:genetics; D004330:Drosophila / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D020271:Heredodegenerative Disorders, Nervous System / Q000378:metabolism*; D006801:Humans; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry*; D020836:Protein Structure, Quaternary / Q000187:drug effects*; D014760:Viral Fusion Proteins / Q000235:genetics
D000914:Antibodies, Viral; D036022:Capsid Proteins; D004268:DNA-Binding Proteins; D019151:Peptide Library; D010455:Peptides; D014760:Viral Fusion Proteins; C097188:polyglutamine