Drug Designing: Open Access
Open Access

Biomolecular Condensates as Drug Targets: The Next Phase in Intracellular Drug Design

Lukas Neumann^{* *}Correspondence: Lukas Neumann, Institute of Molecular Cell Biology and Drug Design, University of Vienna, Vienna, Austria, Email:

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Description

The recognition of biomolecular condensates as critical organizers of cellular biochemistry has opened an exciting frontier in drug discovery. These non-membranous compartments, formed via liquid liquid phase separation, compartmentalize biomolecules such as proteins and RNA into dynamic, often transient assemblies that regulate essential processes like gene expression, signal transduction, and stress responses. Unlike traditional organelles, biomolecular condensates lack physical boundaries and are governed by weak multivalent interactions, enabling rapid reorganization in response to physiological cues. This unique mode of organization offers novel opportunities for therapeutic intervention, especially as aberrant condensate behavior is increasingly linked to diseases such as cancer, neurodegeneration, and viral infection.

Biomolecular condensates serve as microreactors, concentrating substrates, enzymes, or signaling molecules to enhance the specificity and speed of biochemical reactions. The formation and dissolution of these condensates are tightly regulated, with Intrinsically Disordered Regions (IDRs) in proteins playing a critical role in mediating phase separation. Recent studies have shown that alterations in the composition, dynamics, or material properties of condensates can disrupt cellular homeostasis. In cancer, for instance, mutations in proteins like FUS, TAF15, or EWSR1 can alter condensate behavior to drive oncogenic gene expression programs. Similarly, in neurodegenerative diseases such as ALS or frontotemporal dementia, pathological condensates formed by TDP-43 or FUS transition from a liquid to a solid state, leading to toxic protein aggregates. These disease associations make condensates attractive but complex drug targets.

Targeting biomolecular condensates represents a departure from conventional drug design, which typically focuses on well-defined binding pockets within structured proteins. Instead, condensate-targeted drugs must modulate the weak, dynamic interactions that drive phase separation, which are often distributed over large, flexible protein regions. This has led to the emergence of “condensate-modifying agents” small molecules, peptides, or even nucleic acid-based therapeutics designed to influence the assembly, composition, or physical properties of condensates. Such agents may dissolve aberrant condensates, prevent their formation, or alter their dynamics to restore cellular function. For example, recent work has identified small molecules that modulate the behavior of stress granules and nucleoli, two well-characterized condensates involved in RNA metabolism and ribosome biogenesis.

Several innovative strategies have emerged to identify and validate druggable condensates. High-throughput microscopy combined with machine learning is being used to quantify condensate dynamics in live cells. Additionally, biophysical techniques like Fluorescence Recovery After Photobleaching (FRAP) and optical tweezers are employed to assess the material state of condensates, distinguishing between liquid-like and gel-like assemblies. Meanwhile, advances in structural proteomics and proximity labeling allow for mapping the protein and RNA components of condensates with high resolution. These tools facilitate not only target discovery but also the assessment of compound efficacy in modulating condensate behavior.

Pharmaceutical interest in condensates is growing rapidly, with several companies initiating programs specifically focused on condensate biology. Therapeutic areas under investigation include oncology, where MYC-driven transcriptional condensates are targeted to inhibit oncogene expression, and virology, where viral replication factories often phase-separated structures are disrupted to impair infection. In neurodegenerative disorders, the goal is to prevent the pathological maturation of condensates into irreversible aggregates, a hallmark of diseases like Alzheimer’s and Parkinson’s. Importantly, the ability to modulate condensates also opens opportunities for enhancing drug delivery and targeting, by engineering condensate-forming peptides to shuttle therapeutics to specific subcellular compartments.

Despite its promise, condensate-targeted drug design faces significant hurdles. The transient and heterogeneous nature of condensates makes their study and manipulation inherently challenging. Moreover, the field lacks standardized assays for assessing compound effects on condensates, and pharmacological specificity remains a concern — modulating one condensate could inadvertently affect others with shared components. Safety is another key consideration, as condensates regulate vital cellular processes, and their global disruption may lead to unintended toxicity. Therefore, precision in targeting guided by disease-specific biomarkers and condensate-resolved omics is essential for translating this approach into clinically viable therapies.

In conclusion, biomolecular condensates represent a paradigm shift in how we understand intracellular organization and target disease at the molecular level. Their emergence as drug targets reflects a deeper appreciation for the physical principles that govern cellular function beyond static structures. By developing tools and therapeutics that engage with the dynamic, multivalent interactions driving condensate biology, researchers are charting a new course in precision medicine. While the field is still in its infancy, the progress made thus far signals a promising future where modulation of condensate dynamics becomes a cornerstone of innovative drug discovery.