Targeting disorders in unstructured and structured proteins in various diseases

Abstract

Intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) are proteins and protein segments that usually do not acquire well-defined folded structures even under physiological conditions. They are abundantly present and challenge the "one sequence-one structure-one function" theory due to a lack of stable secondary and/or tertiary structure. Due to conformational flexibility, IDPs/IDPRs can bind with multiple interacting partners with high-specificity and low-affinity and perform essential biological functions associated with signalling, recognition and regulation. Mis-functioning and mis-regulation of IDPs and IDPRs causes disorder in disordered proteins and disordered protein segments which results in numerous human diseases, such as cancer, Parkinson's disease (PD), Alzheimer's disease (AD), diabetes, metabolic disorders, systemic disorders and so on. Due to the strong connection of IDPs/IDPRs with human diseases they are considered potentential targets for drug therapy. Since they disobey the "one sequence-one structure-one function" concept, IDPs/IDPRs are complex systems for drug targeting. This review summarises various protein disorder diseases and different methods for therapeutic targeting of disordered proteins/segments. Targeting IDPs/IDPRs for diseases will open up a new era of rational drug design and drug discovery.

Keywords: Cancer; Drug targets; Intrinsically disordered proteins; Neurodegenerative diseases; Protein self-association; Protein-interaction network.