**1. Introduction**

The protein structure–function paradigm was established in the 20th century. The key point of this paradigm is that an ordered (rigid) and unique 3D structure of a protein is an obligatory prerequisite for protein function [1,2]. Nevertheless, recent studies have provided broad and convincing evidences that some proteins do not adopt only one structure, but still are fully functional [3]. The different possible protein conformations are structured (folded), molten globular, pre-molten globular, and unstructured (unfolded) [4].

Since the beginning of the 2000s, a new class of unstructured proteins started to be studied more due to the improvement of techniques to elucidate protein structure. Crystal-structure analysis using X-ray diffraction cannot provide information on unstructured states, with only the absence of electron density in some regions being observed. However, the nuclear magnetic resonance (NMR) technique allowed for the better characterization of these disordered proteins, confirming the flexibility of protein segments that are missing in crystallography experiments [5]. They are defined mainly as intrinsically disordered proteins (IDPs), in spite of some authors defining these proteins as natively denatured [6], natively unfolded [7], intrinsically unstructured [8], and natively disordered proteins [9], among other definitions. We will use the IDP definition to refer to these proteins. The disorder could be also present in some regions of proteins; these regions are named intrinsically disordered regions (IDRs). Intrinsically disordered proteins /IDRs have no single, well-defined equilibrium structure and exist as heterogeneous ensembles of conformers [10].

There are significant differences between the amino acid sequences of IDPs/IDRs in comparison with structured globular proteins and/or domains. These differences are related to amino acid composition, sequence complexity, hydrophobicity, aromaticity, charge, flexibility, type and rate of amino acid substitutions over evolutionary time [11]. Some features of IDPs are the low content of hydrophobic residues and the high load of charged residues [12]. Intrinsically disordered proteins/IDPRs present large hydrodynamic volumes, low content of ordered secondary structure, and high structural heterogeneity. These proteins are very flexible. However, some of them show transitions from the disordered to the ordered state in the presence of natural ligands [10]. The ability of IDPs to return to the highly flexible conformations after performing their biological function, and their predisposition to acquire different conformations according to the environment, are unique properties of IDPs [13] (Figure 1).

**Figure 1.** Example of intrinsically disordered proteins (IDP) conformational plasticity. Shown are ordered and disordered extremes in the conformational ensemble described for the photoactive yellow protein from *Halorhodospira halophile* (PDB IDs 3PHY and 2KX6).

It was demonstrated that these IDPs are highly prevalent in many genomes, including humans', and are important in several cellular processes, such as regulation of transcription and translation, cell cycle control, and signaling [3]. It is important to highlight that they are much more common in eukaryotes, in comparison to Eubacteria and Archaea, reflecting the greater importance of disorder-associated signaling and regulation for eukaryotic cells [13]. Intrinsically disordered proteins are present in major disease pathways, such as cancer, amyloidosis, diabetes, cardiovascular, and neurodegenerative diseases. Changes in the environment and/or mutation(s) of IDPs would be expected to affect their normal function, leading to misidentification and missignaling. Consequently, it can result in misfolding and aggregation, which are known to be associated with the pathogenesis of numerous diseases. Some IDPs, such as α-synuclein, tau protein, p53, and BRCA1 are important in

neurodegenerative diseases and cancer, being attractive targets for drugs modulating protein–protein interactions. Based on these IDPs and other examples, novel strategies for drug discovery have been developed [11,13]. The ability to modulate the interactions of these proteins offers tremendous opportunities of investigation in chemical biology and molecular therapeutics. Several recent small molecules, such as potential drugs, have been shown to act by blocking protein–protein interactions based on intrinsic disorder of one of the partners [14].

In this review, we will focus on IDPs involved in some neurodegenerative diseases, such as α-synuclein, amyloid β-peptide, and tau protein, while also commenting on cancer associated IDPs, such as p53 and c-Myc, and diabetes-related amylin. In addition, we will summarize the strategies to modulate IDPs action in some diseases and the promising drugs in this field, which are currently more developed for non-neurodegenerative disorders, prompting the need of focusing strategies on IDP-centered drug development for them.
