Principles and functions of condensate modifying drugs

Abstract

Biomolecular condensates are compartmentalized communities of biomolecules, which unlike traditional organelles, are not enclosed by membranes. Condensates play roles in diverse cellular processes, are dysfunctional in many disease states, and are often enriched in classically "undruggable" targets. In this review, we provide an overview for how drugs can modulate condensate structure and function by phenotypically classifying them as dissolvers (dissolve condensates), inducers (induce condensates), localizers (alter localization of the specific condensate community members) or morphers (alter the physiochemical properties). We discuss the growing list of bioactive molecules that function as condensate modifiers (c-mods), including small molecules, oligonucleotides, and peptides. We propose that understanding mechanisms of condensate perturbation of known c-mods will accelerate the discovery of a new class of therapies for difficult-to-treat diseases.

Keywords: biomolecular condensates; condensate modifying drugs (c-mods); condensatopathy; dissolvers; inducers; localizers; morphers.

FIGURE 1

c-mod classes. A schematic representation of the optical phenotypes of condensate modification used to classify c-mods. Dissolvers drive dissolution of an existing condensate. Inducers cause assembly of a new condensate. Localizers alter the localization of specific condensate community members. Morphers alter the physiochemical properties of an existing condensate.

FIGURE 2

A chemically diverse set of bioactive molecules act as c-mods. (A) The default t-SNE projection of small molecules by applying rdkit fingerprints; the molecules are reported in Table 1; the molecule names are colored according to the c-mod classes shown in Figure 1. The 2D structure of representative small molecules are shown. (B) A representative of the dissolver c-mod class, The NIP-V peptide sequence (gold) binds to the dimerization domain (DD) of the SARS2-NP (PDB ID: 7C22), A Tat-fusion (in black) was included in NIP-V to facilitate cellular uptake. (C) and (D) Representatives of the inducer c-mod class. (C) Nusinersen ASO structure, downloaded from PubChem, was energy minimized and the lowest energy conformer was searched using Molecular Operating Environment (MOE 2020.0901). (D) The cryo-EM structure of BCL6-BTB filament in complex with BI-3802 (PDB ID: 6XMX) and binding conformation of BI-3802 in BCL6.