Intrinsically disordered proteins and biomolecular condensates as drug targets

Abstract

Intrinsically disordered domains represent attractive therapeutic targets because they play key roles in cancer, as well as in neurodegenerative and infectious diseases. They are, however, considered undruggable because they do not form stable binding pockets for small molecules and, therefore, have not been prioritized in drug discovery. Under physiological solution conditions many biomedically relevant intrinsically disordered proteins undergo phase separation processes leading to the formation of mesoscopic highly dynamic assemblies, generally known as biomolecular condensates that define environments that can be quite different from the solutions surrounding them. In what follows, we review key recent findings in this area and show how biomolecular condensation can offer opportunities for modulating the activities of intrinsically disordered targets.

Keywords: Biomolecular condensates; Drug discovery; Free energy landscape; Intrinsically disordered proteins.

Figure 1

Generic free energy landscape of an intrinsically disordered protein with a propensity to condensate where the free energy of a protein molecule (G) is represented as a function of its degree of structuration (s) and multimerization (n). The letters represent the different minima that may be populated by such molecule, that are illustrated by representative conformations and include highly disordered state (D), partially and fully structures states (PS, FS), an oligomeric state (O), a biomolecular condensate (BC), a hydrogel (HG) and a fibril (F). Changes in the free energy of any state caused by interaction with a small molecule can lead to population shifts or changes in kinetic stability that can be used to alter the propensity of the protein to interact with a binding partner, form condensates or form fibrillar aggregates as shown in Figure 2.

Figure 2

a) Energy landscape of an intrinsically disordered protein before and after small molecule binding illustrating how it can inhibit protein-protein interactions, provide kinetic stability against fibril formation as well as cause population shifts that promote or suppress biomolecular condensation. b) Schematic illustration of a generalized mechanism for the interaction between small molecules and intrinsically disordered proteins derived from both experimental and computational studies. c) Schematic representation of a biomolecular condensate, of the exchange of protein molecules from the biomolecular condensate to the surrounding solution and of the effect of small molecule binding to an intrinsically disordered protein undergoing biomolecular condensation according to the polyphasic linkage framework.