With few exceptions, a protein must adopt a specific three-dimensional structure in order to function properly. This final structure is achieved through a dynamic process known as protein folding that is directed by several factors, including the protein’s primary amino acid sequence, the functions of other proteins that influence specific steps on the folding pathway, and the folding environment. Alterations in any of these elements may cause the protein to adopt an abnormal, misfolded structure. Protein misfolding is believed to be central to the pathology of many important human diseases, including cancer, Alzheimer’s disease, Parkinson’s disease, and cystic fibrosis.
Protein misfolding causes disease in one of two ways – either from the loss of essential protein function, or from the accumulation and aggregation of toxic species.
The protein p53 plays a central role in triggering programmed cell death (also known as apoptosis) in cells that are beginning to display hallmarks of cancerous growth. This key “tumor suppressor” protein is mutated in more than half of all cases of human cancer. It is now understood that the majority of p53 mutations cause the protein to misfold, adopt a non-native conformation, and lose function. Without properly functioning p53, cancerous cells are able to evade an important regulatory mechanism allowing them to grow unchecked. and to resist many front-line therapies.
Similarly, a high percentage (>90%) of cystic fibrosis patients have a single mutation (ΔF508) in the gene encoding the CFTR protein that causes misfolding, consequent destruction by the cellular quality control machinery, and loss of essential function. Without properly functioning CTFR protein, cells are unable to transport chloride ions across epithelial cell membranes, which results in significant breathing and digestion problems.
The pathological hallmark of Alzheimer’s disease (AD) is the presence in the brain of amyloid plaques containing high levels of the protein Aβ. Although much attention has been focused on the role of these plaques in AD pathology, it is now widely recognized that oligomers of Aβ, the precursors of the amyloid plaques, are the likely toxic species that drive neurodegeneration in AD. Similarly, aggregation of the microtubule-associated protein tau is implicated in the pathology of AD and a number of other neurodegenerative diseases. Misfolding and aggregation of α-synuclein, SOD1, and huntingtin are implicated in the pathologies of Parkinson’s disease, ALS, and Huntington's disease, respectively.
Misfolding is often a prerequisite for aggregation, in part because it exposes hydrophobic amino acid residues, normally buried in the protein’s core, to the aqueous environment of the cytosol. As a result, the protein loses solubility and is predisposed toward self-association.
A proven approach for correcting protein misfolding is the addition of a “Molecular Chaperone” – a compound that binds to the protein and helps it to fold in the proper conformation. The identification of small molecule drugs that can function as molecular chaperones represents an exciting new area of biology. Such drugs would impact the true underlying cause of important diseases by restoring normal biological function or preventing the formation of toxic aggregrates.
Reata has a proprietary method for identifying molecular chaperones and is pursuing discovery research programs to find drugs that correct misfolding of several important biological targets. |
