Modulating biomolecular condensates: a novel approach to drug discovery

Abstract

In the past decade, membraneless assemblies known as biomolecular condensates have been reported to play key roles in many cellular functions by compartmentalizing specific proteins and nucleic acids in subcellular environments with distinct properties. Furthermore, growing evidence supports the view that biomolecular condensates often form by phase separation, in which a single-phase system demixes into a two-phase system consisting of a condensed phase and a dilute phase of particular biomolecules. Emerging understanding of condensate function in normal and aberrant cellular states, and of the mechanisms of condensate formation, is providing new insights into human disease and revealing novel therapeutic opportunities. In this Perspective, we propose that such insights could enable a previously unexplored drug discovery approach based on identifying condensate-modifying therapeutics (c-mods), and we discuss the strategies, techniques and challenges involved.

YAP condensates are highly organized hubs for YAP/TEAD transcription

“…These methods, while often effective in disrupting condensates of interest, suffered from high toxicity and a lack of specificity. Recently, new methods have emerged to target disease-causing condensates, including modulating condensate composition, targeting the molecular interactions among condensate components, and modulating condensate regulatory processes 51,55 . Despite this progress, and the potential involvement of YAP condensates in cancer, there is currently no effective way to modulate YAP condensates.…”

Principles and functions of condensate modifying drugs

“…Modulation of condensate properties and function can be achieved in several ways, including, but not limited to the classes we introduced (dissolvers, inducers, localizers and morphers). C-mods can act directly with condensate components (direct c-mods) or upstream, on targets that modify condensate components, such as PTM enzymes (indirect c-mods) ( Kilgore and Young, 2022 ; Mitrea et al, 2022 ).…”

“…Communities of biomolecules including nucleic acids, metabolites, and proteins assemble via extensive interaction networks, on length scales of nanometers to micrometres, locally concentrating selected components. The physicochemical properties of a condensate arise from the emergent properties of the molecular community (reviewed in ( Banani et al, 2017 ; Lyon et al, 2021a ; Mitrea et al, 2022 )). Importantly, proteins containing long intrinsically disordered regions (IDRs) are highly enriched in condensates.…”

“…Aberrant disruption of any one of these parameters can lead to a pathogenic cellular state, so the same pathogenic endpoint can be reached by deregulating a condensate via disparate mechanisms. In these cases, condensates serve as integrating nodes of disease ( Mitrea et al, 2022 ). We define a “condensatopathy” as an aberration of a condensate that drives a specific disease phenotype.…”

“…We define a “condensatopathy” as an aberration of a condensate that drives a specific disease phenotype. Notably, as defined, a condensatopathy can be causative or strongly associated with a particular disease ( Mitrea et al, 2022 ). Thus, condensates have emerged as appealing drug targets.…”