Identification of inhibitors of biological interactions involving intrinsically disordered proteins

Abstract

Protein-protein interactions involving disordered partners have unique features and represent prominent targets in drug discovery processes. Intrinsically Disordered Proteins (IDPs) are involved in cellular regulation, signaling and control: they bind to multiple partners and these high-specificity/low-affinity interactions play crucial roles in many human diseases. Disordered regions, terminal tails and flexible linkers are particularly abundant in DNA-binding proteins and play crucial roles in the affinity and specificity of DNA recognizing processes. Protein complexes involving IDPs are short-lived and typically involve short amino acid stretches bearing few "hot spots", thus the identification of molecules able to modulate them can produce important lead compounds: in this scenario peptides and/or peptidomimetics, deriving from structure-based, combinatorial or protein dissection approaches, can play a key role as hit compounds. Here, we propose a panoramic review of the structural features of IDPs and how they regulate molecular recognition mechanisms focusing attention on recently reported drug-design strategies in the field of IDPs.

Figure 1

Apurinic/apyrimidinic endonuclease 1 (APE1). (A) Schematic representation of its modular structure. NLS: Nuclear Localization Signal; (B) Prediction of disorder tendency of hAPE1 sequence with PONDR-FIT; and (C) Multiple sequence alignment of the N-terminal region of APE1 mutants analyzed in reference [39]; positively charged amino acids are reported in bold while insertional mutations are underlined.

Figure 2

Nucleophosmin 1 (NPM1). (A) Schematic representation of its structure. AD: Acidic Domain; BD: Basic Domain; NoLS: Nucleolar Localization Signal; (B) Prediction of disorder tendency of NPM1 sequence with PONDR-FIT; and (C) Sequences of central intrinsically disordered regions of protein; positively charged amino acids are reported in bold.