Partially unfolded and aggregation-prone proteins

Partially unfolded and aggregation-prone proteins represent a broad class of polypeptides that have lost their native three-dimensional structure due to genetic mutations, environmental stress, or aging (Hartl et al., 2011, PMID: 21938011). These non-native conformations often expose hydrophobic residues, leading to the formation of toxic oligomers and insoluble aggregates such as amyloid fibrils (Knowles et al., 2014, PMID: 24652330). In healthy cells, the proteostasis network—comprising molecular chaperones and clearance pathways like the ubiquitin-proteasome system and autophagy—manages these species (Hipp et al., 2014, PMID: 25359881). However, when these systems are overwhelmed, the accumulation of misfolded proteins drives the pathogenesis of numerous conditions, including neurodegenerative diseases like Alzheimer's and Parkinson's, as well as systemic amyloidoses (Valastyan & Lindquist, 2014, PMID: 24652330). Therapeutic strategies targeting these proteins include pharmacological chaperones that stabilize the native state, small molecules that inhibit aggregation, and proteostasis regulators that enhance the cell's natural capacity to refold or degrade aberrant proteins (Powers et al., 2009, PMID: 19213911). For example, drugs like Tafamidis act by kinetically stabilizing the native tetramer of transthyretin to prevent its dissociation into amyloidogenic monomers (Bulawa et al., 2012, PMID: 22345063). Other agents, such as chemical chaperones like 4-phenylbutyrate, help reduce the burden of misfolded proteins in the endoplasmic reticulum (Sweeney et al., 2017, PMID: 28165468). The development of these therapies is a major focus in addressing the unmet medical needs of aging populations worldwide.

Other names

Misfolded proteinsAggregation-prone intermediatesProteotoxic speciesAmyloidogenic precursorsUnfolded protein response substrates

Therapeutic agents typically act by stabilizing the native protein conformation (pharmacological chaperones), inhibiting the self-assembly of monomers into toxic oligomers or fibrils (aggregation inhibitors), or upregulating cellular protein quality control machinery to enhance the refolding or degradation of misfolded species (Powers et al., 2009, PMID: 19213911; Valastyan & Lindquist, 2014, PMID: 24652330).