Cell biologists are exploring and exploiting protein-folding pathways as a source of drug targets for diseases involving disruption of protein homeostatis, or proteostasis.
Such diseases affect proteome expression, protein function, and proteome maintenance. The “American Society for Cell Biology” (ASCB) annual meeting featured presentations that illustrated how managing the protein fold can modify local proteostasis activity to intervene in protein folding, degradation, and function across a range of human diseases including cancer, cystic fibrosis, and neurodegenerative diseases.
One researcher who spoke at the meeting was Jeffery Kelly, Lita Annenberg Hazen Professor of Chemistry and chairman, department of molecular and experimental medicine at the Scripps Institute. Dr. Kelly’s lab studies proteostasis from the perspective of the competition between protein folding, misfolding, and aggregation, and the link between diseases and protein misfolding coupled to degradation or aggregation.
His team then designs small molecules to enhance biological protein maintenance mediated by the proteostatis network, for example, by enhancing protein folding and trafficking or promoting clearance of misfolding- or aggregation-prone proteins. A complementary chemical approach creates a small molecule that binds to the native state of a specific misfolding-prone protein to prevent misfolding and aggregation. The latter strategy has led to the discovery of a first-in-class small molecule drug to treat gain-of-toxic-function transthyretin amyloid diseases associated with neuro- and cardio-degeneration.
Specifically, Dr. Kelly described the development of the drug tafamidis (Vyndaqel, FoldRx/Pfizer), which recently received approval by the EMA and is under review by the U.S. FDA. This drug, developed using structure-based design principles, binds to a site at the dimer-dimer interface of the native tetrameric structure of the protein transthyretin.
In the gain-of-toxic-function transthyretin amyloid diseases, aberrant dissociation of the tetramer allows the misfolded monomers to aggregate outside the cell. In this autosomal dominant disease, the mutant and wild-type (wt) subunits produced by heterozygotes are able to form heterotetramers that can evade the cellular quality control system and are secreted from the cell. However, these tetramers are less stable than their wt-wt counterparts and more readily dissociate once secreted, facilitating toxic amyloid formation.
Dr. Kelly’s group targeted the weaker of the dimer-dimer interfaces and crafted a small molecule that binds with high affinity and specificity and prevents the tetramer from dissociating outside the cell, thereby inhibiting protein aggregation and amyloid formation.
Amyloid pathology plays a key role in several degenerative diseases, including peripheral nervous system disorders and cardiomyopathies. “Tafamidis is the only approved drug targeting the underlying cause of an amyloid disease,” reports Dr. Kelly. The potential for these types of drugs “is huge,” he adds. “Protein misfolding or aggregation is a component of diseases that “span virtually every therapeutic area, from eye, to kidney, metabolic, heart, and neurodegenerative diseases.”