Allosteric drugs in biomolecular condensates: Ways forward

• Two allosteric drug classes exist, which differ in their mechanism and specificity. • The less-specific Class I includes drugs targeting the condensate environment. • The highly specific Class II targets the mechanism of condensate-resident proteins. • Adapting Class II drugs to condensate environments can lead to more effective therapies. • We evaluate and suggest strategies to adapt Class II drugs to the condensate environment. • We suggest a combination of Class I and condensate-optimized Class II drugs. Biomacromolecular condensates are membraneless compartments that form through the dynamic assembly of function-related macromolecules to perform specific functions, such as signaling and gene expression. They have crucial roles in disease, fueling significant interest in their therapeutic potential. Efforts largely focus on condensate-modulating drugs, disrupting the crowded, interlinked molecular mesh. Although this is an important aim, such drugs might not be as specific as ‘classical’ allosteric drugs, and it remains challenging to optimize highly specific allosteric drugs. Condensate-resident proteins are intimately linked to allosteric behavior, making allosteric drugs, which are highly specific, their prioritized targets. This work examines the two classes of allosteric drugs, exploring how biomolecular condensates can be leveraged to advance a new era of condensate-adapted, protein-specific allosteric drug discovery.