Chemical Biology: Approaches to Drug Discovery and Development to Targeting Disease

Chapter 19: Protein Misfolding and Disease

Johanna C. Scheinost

Grant E. Boldt

Paul Wentworth jr.

The Scripps–Oxford Laboratory, Department of Biochemistry, University of Oxford, UK

Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute La Jolla CA

The amyloidoses are a class of conformational diseases that arise from the conversion of normally unfolded or globular proteins into fibrillar aggregates that are either pathogenic or nonfunctional. At present there are more than 20 proteins that are associated with human amyloid diseases. This review focuses on three natively unfolded proteins that form fibrillar aggregates; amyloid-β, islet amyloid polypeptide (“amylin”), and α-synuclein, the diseases they contribute to and chemical and biophysical approaches that are used to investigate these proteins' aggregation.

19.1 Introduction

Conversion of native conformational folded proteins or peptides into highly-ordered insoluble fibrillar aggregates termed “amyloid” has been demonstrated to be clinically-relevant in several diseases. Misfolded proteins are deposited in a variety of tissues, leading to serious and even fatal human diseases. To date there are over 20 proteins and peptides that are known to induce pathological conditions associated with protein misfolding (Table 19.1). These proteins include the amyloid-β peptides, prion proteins, α-synuclein, transthyretin and polyglutamine-containing peptides [1]. The hypothesis that these ...