Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

Abstract

Self-aggregation of proteins and peptides is at the root of many diseases, especially neurodegenerative diseases. These conditions include Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, type-2 diabetes mellitus, and transmissible spongiform encephalopathies, which are associated with self-aggregation of amyloid β-protein (Aβ), huntingtin, α-synuclein, islet amyloid polypeptide, and the prion protein, respectively. The list of diseases for which protein/peptide aggregation is the root cause is ever expanding. There does not appear to be a single biochemical mechanism by which proteins and peptides self-associate, or a single pathogenic mechanism to explain all protein-/peptide-aggregation diseases. Nevertheless, inhibition of protein self-aggregation remains a potential target for therapeutic intervention. Beyond therapy, inhibitors of protein self-aggregation can serve as tools to help us understand the mechanisms by which aggregation occurs and harms cells. In this chapter, we examine select examples of inhibitors of protein aggregation. We have divided aggregating proteins/peptides into two types: (1) Proteins that have an unstable tertiary structure, that unfold under cellular stress, or that fail to fold correctly during biosynthesis. This instability leads to persistence of unfolded domains that can act as a nidus for self-association. (2) Peptides or proteins (or protein domains) that cannot fold at all, or fold only in the presence of a bound ligand. Examples of the first group include transthyretin, the mammalian prion protein, and certain point-mutant forms of lysozyme or α1-antitrypsin. In general, self-aggregation of these proteins results from exposure of normally buried hydrophobic residues to aqueous media. Examples of the second group include Aβ, islet amyloid polypeptide, and calcitonin. Within the second group, we also include proteins that are “peptide-like” in having domains with no unique, stable tertiary fold, such as huntingtin and α-synuclein. The category of peptides and “peptide-like” proteins can be further subdivided into those containing unburied hydrophobic residues (e.g., Aβ), and those with strings of hydrogen-bonding polar residues (e.g., huntingtin and other polyglutamine proteins). To reduce the sheer volume of material in this field, we have chosen to focus mainly on one example of each type of aggregating protein or peptide, i.e., Aβ, as a peptide aggregating through the hydrophobic effect; huntingtin, as a peptide-like protein aggregating through side-chain and peptide backbone hydrogen bonding; and transthyretin, as a protein with an unstable tertiary fold. The mechanisms of self-aggregation serve as a guide for developing aggregation inhibitors. Inhibitors run the gamut of peptides, including natural and synthetic peptides, and those containing non-natural amino acids; proteins, both natural and engineered; and small molecules, including both natural and synthetic substances. The pursuit of aggregation inhibitors remains a prime goal in the search for treatments of protein aggregation diseases. In spite of some serious setbacks in clinical trials, the outlook remains bright—but the continuing task calls for equal measures of perseverance and theraeutic, as well as intellectual, modesty.