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.

Global Discovery of Covalent Modulators of Ribonucleoprotein Granules

“…An advantage of using covalent small molecules for ligand discovery is rapid target and binding site identifications using quantitative chemical proteomics. Target deconvolution represents an important, but often challenging, first step toward understanding mode of action for condensate-modifying compounds. , The binding profiles obtained from chemical proteomics enable global selectivity profiling and bioinformatics-mediated discovery of enriched protein functions and domains underlying the PB- and SG-modulating activity of hit compounds.…”

“…Compounds that target SG proteins have been reported, but direct binding remains to be demonstrated . Thus, apart from approved drugs with condensate modifying activity discovered after the fact, RNP granule modulators consist largely of toxic compounds or lead hits from HTS that lack known direct binding targets.…”

Secretory Phospholipases A2, from Snakebite Envenoming to a Myriad of Inflammation Associated Human Diseases—What Is the Secret of Their Activity?

“…Knowing the interactions and any molecular condensates in which sPLA2 is involved is of paramount importance. Molecular condensates regulate a variety of cellular activities and are involved in numerous pathological processes [ 69 , 91 ], therefore, they are being studied for the development of molecules that can induce their formation, alter, or even dissolve them [ 92 ].…”

Macromolecular crowding is surprisingly unable to deform the structure of a model biomolecular condensate

“…[17][18][19][20][21] Experiments on BCs have advanced to the point that they are being synthetically designed to modulate biochemical and cellular functions, [22][23][24][25][26][27][28] and mined for novel drug targets. [29][30][31] A better understanding of how BCs are coupled (or not) to their crowded environment would assist in deciphering their cellular roles and constructing synthetic BCs. [32][33][34][35][36][37][38] The complexity of living cells has driven research on model condensates, which typically use unphysiologically-high concentrations of one, or at most a few, species of IDP in buffer, although their relevance to living cells has been strongly questioned.…”

“…[17-21] Experiments on BCs have advanced to the point that they are being synthetically designed to modulate biochemical and cellular functions,[22-28] and mined for novel drug targets. [29-31] A better understanding of how BCs are coupled (or not) to their crowded environment would assist in deciphering their cellular roles and constructing synthetic BCs. [32-38]…”