Therapeutics—how to treat phase separation-associated diseases

Abstract

Liquid–liquid phase separation has drawn attention as many neurodegeneration or cancer-associated proteins are able to form liquid membraneless compartments (condensates) by liquid–liquid phase separation. Furthermore, there is rapidly growing evidence that disease-associated mutation or post-translational modification of these proteins causes aberrant location, composition or physical properties of the condensates. It is ambiguous whether aberrant condensates are always causative in disease mechanisms, however they are likely promising potential targets for therapeutics. The conceptual framework of liquid–liquid phase separation provides opportunities for novel therapeutic approaches. This review summarises how the extensive recent advances in understanding control of nucleation, growth and composition of condensates by protein post-translational modification has revealed many possibilities for intervention by conventional small molecule enzyme inhibitors. This includes the first proof-of-concept examples. However, understanding membraneless organelle formation as a physical chemistry process also highlights possible physicochemical mechanisms of intervention. There is huge demand for innovation in drug development, especially for challenging diseases of old age including neurodegeneration and cancer. The conceptual framework of liquid–liquid phase separation provides a new paradigm for thinking about modulating protein function and is very different from enzyme lock-and-key or structured binding site concepts and presents new opportunities for innovation.

Liquid–Liquid Phase Separation by Intrinsically Disordered Protein Regions of Viruses: Roles in Viral Life Cycle and Control of Virus–Host Interactions

“…This opens some potential routes for designing novel antiviral drugs that would affect the phase-separation potential of viral proteins. Although the therapeutic means for curing phase separation-associated diseases are in general at the very early stages of their development, we agree with the envision that "the conceptual framework of LLPS provides a new paradigm for thinking about modulating protein function" and, therefore, opens new opportunities to design innovative drugs [236]. There are two major approaches that can be potentially utilized for the treatment of phase separation-associated diseases, including viral infections, which consist in targeting two different types of players engaged in biological LLPS, namely "drivers" and "controllers".…”

“…Furthermore, aberrant PTMs can cause abnormal LLPS, associated with the pathogenesis of phase separation-associated diseases [239,245]. Furthermore, since the concentration of the drivers is the crucial factor driving LLPS, another obvious set of controllers to be targeted is that of the regulators of protein biosynthesis, degradation, and transport [236]. The involvement of such controllers in the overall protein turnover and transport makes the task of identifying the appropriate target very challenging [236].…”

Altered Phase Separation and Cellular Impact in C9orf72-Linked ALS/FTD

“…Two molecules which have recently shown promise for ALS are lipoamide and lipoic acid which prevent FUS aggregation via influencing FUS phase separation and reduce FUS toxicity in vivo (Wheeler et al, 2019). The identification of small molecules and compounds that can modulate the charge-charge and cation-pi interactions essential for phase separation of LCD containing proteins is an interesting avenue for future research, although a greater understanding is needed into the physiochemical mechanisms as to how molecules such as lipoamide and lipoic acid disrupt these interactions inhibiting LLPS (Wheeler, 2020). Again, post-translational modifications can be targeted.…”

FtsZ Interactions and Biomolecular Condensates as Potential Targets for New Antibiotics

“…FtsZ biomolecular condensates may therefore constitute additional targets to be considered in the search for new antimicrobials, as it has been recently proposed for condensates involved in different diseases [ 155 ]. Drug candidates that modulate the formation of these structures may alter cell functionality and, more importantly, they may lead to novel strategies to combat persistence, a major health threat.…”