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<p>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.</p>

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Targeting protein disorder: the next hurdle in drug discovery

  • 期刊论文

  • 发表日期：

    2025年6月9日

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  • Tamas Lazar,
  • Acadia Connor,
  • Charles F. DeLisle,
  • Virginia Burger,
  • Peter Tompa

摘要

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.