Abstract
Intrinsically disordered proteins have key signalling and regulatory roles in cells and are frequently dysregulated in diseases such as cancer, neurodegeneration, inflammation and autoimmune disorders. Preventing the pathological functions mediated by structural disorder is crucial to successfully target proteins that drive transcription, biomolecular condensation and protein aggregation. However, owing to their heterogeneous, highly dynamic structural states, with ensembles of rapidly interconverting conformations, disordered proteins have been considered largely ‘undruggable’ by traditional approaches. Here, we review key developments of the field and suggest that the synergy of advanced experimental and computational approaches needs to be pursued to conquer this barrier in drug discovery.
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Acknowledgements
This work was implemented with support from the National Research, Development and Innovation Fund of the Ministry of Culture and Innovation under the RGH_24 (RGH 151464) Grant Agreement with the National Research, Development and Innovation Office, Hungary, and grants from the National Research, Development and Innovation Office, Hungary (NKFIH, no. K124670 and K131702) to P.T. T.L. is holder of a postdoctoral innovation mandate (grant no. HBC.2022.0194) from the Flanders Innovation & Entrepreneurship Agency (VLAIO). T.L. and P.T. also thank the members of the ELIXIR Intrinsically Disordered Protein Community and the ML4NGP COST Action (CA21160) consortium for the fruitful discussions relevant to the topic of the article.
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T.L. conceived and wrote the manuscript, created figures, read and corrected the manuscript; A.C. conceived and wrote the manuscript, created figures, read and corrected the manuscript; C.F.D. conceived and wrote the manuscript, created figures, read and corrected the manuscript; V.B. conceived and wrote the manuscript, created figures, read and corrected the manuscript; P.T. conceived and wrote the manuscript, created figures, read and corrected the manuscript.
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V.B. and P.T. were co-founders and former board members of New Equilibrium Biosciences, and A.C. and C.F.D. were employees at New Equilibrium Biosciences, an IDP-targeting drug discovery company that was dissolved in 2023. Currently, V.B. is employed at Blackbird Laboratories. A.C. is a full-time employee of Versatope Therapeutics. C.F.D. is a full-time employee of Malvern Panalytical. The other author declares no competing interests.
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Glossary
- Binding pockets
-
Specific regions of the surface of a protein involved in binding to small molecules, such as a substrate, coenzyme, ligand or drug molecule. Identifiable by mutations and direct binding analyses, they differ in terms of amino acid distribution, hydrophobicity and convexity from the rest of the protein surface.
- Biomolecular condensation
-
A term used interchangeably with phase separation especially as applied to biologically relevant processes, leading to the formation of biomolecular condensates, such as membraneless organelles, chromatin, nuclear pore, the cytoplasmic portions of membrane protein clusters and the extracellular matrix.
- Condensatopathies
-
Aberrations of biomolecular condensates that drive specific disease phenotypes observed in vitro or in vivo. They result from aberrant formation, overactivation or altered material state of the condensate, or mislocalization of key components.
- Conformational ensemble
-
The set of rapidly interconverting conformations adopted by a disordered protein, each found at a local free energy minimum. More than one ensemble can comply with a given set of experimental observables.
- Conformational selection
-
A process whereby partner binding by a disordered region occurs by the binding-competent conformation that is present in the conformational ensemble. If the structural transition occurs after binding, it is termed induced folding.
- Entropic chains
-
A function unique to intrinsically disordered proteins derived directly from the disordered state, for example, via exerting force or providing spatial confinement for flanking regions beyond the disordered region.
- Globular proteins
-
Also globular domains. Fully structured or ‘folded’ proteins, or those with structured regions.
- Induced folding
-
A process whereby a disordered binding region undergoes transition to a structured partner-bound state following engagement with the partner. If the transition occurs before binding, it is termed conformational selection.
- Intrinsic structural disorder
-
The polypeptide chain of many proteins, or regions, does not take a stable, folded structure, but remains unfolded or disordered for part of their lifetime. They are structurally characterized as a conformational ensemble, sometimes oversimplified as a random coil.
- Intrinsically disordered proteins and regions
-
(IDPs and IDRs). A protein that is structurally disordered along its entire length is most often termed an IDP, whereas if only a region of it is disordered, an IDR. Proteins are often a mixture of globular domains and IDRs.
- Low-complexity domains
-
(LCDs). Stretches of protein that contain a limited set of amino acids and/or have internal sequence repeats. LCDs often, but not always, occur within intrinsically disordered proteins or regions.
- Phase separation
-
A physical process in which a solution of macromolecules (often a mixture of proteins and RNA) demixes into two phases, one depleted, the other enriched in concentration. Also termed biomolecular condensation (and in a narrow sense, liquid–liquid phase separation), it gives rise to biomolecular condensates in the cell.
- Random coils
-
Completely ‘disordered’ conformational state of intrinsically disordered proteins or regions in which residues are oriented randomly relative to one another. A protein in a random-coil state samples all possible conformations randomly (the free energy landscape has no substantial local minimum, but is essentially flat), without any short- or long-range constraints of distance or orientation.
- Short linear motifs
-
(SLiMs). Conserved, linear sequences of amino acids (also termed eukaryotic linear motifs), most often within intrinsically disordered proteins or regions, that mediate recognition and targeting activities of the protein. SLiM function is most often realized by folding that is induced upon binding to a cognate recognition ___domain, so a 3D structure of the parent protein is not necessarily helpful.
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Lazar, T., Connor, A., DeLisle, C.F. et al. Targeting protein disorder: the next hurdle in drug discovery. Nat Rev Drug Discov (2025). https://doi.org/10.1038/s41573-025-01220-6
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DOI: https://doi.org/10.1038/s41573-025-01220-6
